- While the Blood+ anime is marked with the deaths of important characters like - Riku, Solomon, George; in the Blood+ manga, they are shown to be alive.
- In the anime, James dies in New York and has plenty of fights with Saya beforehand; James dies on the very first encounter with Saya on Red Shield HQ deck in the manga.
- Diva forcefully mates with Riku and they have daughters in anime; Riku and Diva never mates on the manga - so no children there.
- Riku is able to hear Diva's song and is scared of her; the manga shows Riku to want to save Diva from Saya.
- Mui is Riku's vietnamesse friend and she is shown alive as part-chiropteran in the anime; in the manga Mui is shown as Saya's friend and is killed by Saya after fully turning into a chiropteran.
- Diva dies in Saya's hands according to the anime; Nathan kills Diva on the manga.
- Nathan is the strongest and the most mysterious character as per shown in the anime; whereas in the manga he is savagely killed by an enraged Saya after he kills Diva plunging sword into her through Saya.
- There is no Karl Fei-Ong in the manga, although it has been explained that Carl was renamed Charles by Amshel.
- There are no schiffs in the manga.
- Many minor characters like- Glay, Min, Monique, Liza never appear in the manga.
- The corpse corps on the anime are Moses' clones; in the manga, they are made as Charles' clones.
- Solomon happened to be Diva's most favorite chevalier in anime; however, Carl was Diva's favorite in the manga.
- Solomon in the anime loves Saya so much that he died as her chevalier creating a bond beyond blood; in the manga version, he is showed to be more scientist-like, experiment clinging as he tells Van that he'll wait for the next 30 years for Saya to wake up so he can do the mating experiment with her.
- David never gets drunk in the manga.
- Diva is showed to hold a grudge against Saya in the anime but on the manga, she is quite obsessed and inclined to her sister.
- Van Argiano is showed as a much serious character throughout the manga, he is also the one to save Solomon in the end.
- Saya is depicted as a much stronger fighter than others in the manga while the anime Saya really struggles to keep up even with chevaliers.
- The scenario in which Haji becomes Saya's chevalier differs greatly between the anime and manga versions. In the anime Haji nearly dies because he climbs down a cliff and falls while trying to pick a flower that Saya wanted for Joel's birthday. In the manga however, it is Diva that nearly kills Haji by impaling his chest out of jealousy.
- While Saya is shown traveling to many different places in the anime, she only goes to Vietnam and finally New York in the manga.
- Rather than the one-year time skip occuring after Saya and Hagi's disappearence, only three months have passed in the manga.
- David appears to be very resentful of Saya for killing his father and sees her as nothing more than a weapon.
- When Kai wishes to learn of Saya's history, he threatens Joel Goldschmidt VI with a broken piece of glass.
- After Riku becomes a chevalier and Saya is fully awakened, she becomes much colder to Kai and those around her, even Hagi.
- Hagi is portrayed as being jealous and possesive towards Saya.
- Mao Jahana plays an even lesser role as she is only seen in the first volume.
- Saya and Riku are seen getting bullied by other students who taunt them for being adopted.
- Riku gets kidnapped twice.
- After getting his armed severed by a berserk Saya during the Vietnam War, Charles is demoted from Chevalier status by Amshel and is banned from seeing Diva ever again.
- The chevaliers never transform into full chiropterans and all seem to possess the ability to change their limbs in the same manner as Solomon.
- When Red Shield HQ is destroyed, Joel is never injured and therefore not bound to a wheelchair.
- While Kai is still protective of his sister, he sometimes displays a lecherous attitude towards her.
- Cinq Flèches is never found out for the experiments they conducted on humans and Van is therefor never arrested.
- Though they are in the same location, the Metropolitan Opera House is simply reffered to as 'Lincoln Center'.
- Characters like Okamura and Archer do not appear.
- Collins makes only one brief appearance in the manga.
- Julia and Collins never betray Red Shield.
- Riku's death differs greatly in this adaptation. Here, he is shot by Van while trying to protect Charles.