This is one of the strongest of Orochimaru's Cursed Seals, the other being its counterpart, the Cursed Seal of Earth. The seal consists of three tomoe, similar to the Sharingan, which, when activated, spread like flames across the user's body. When Sasuke activated the second level of the seal, his skin turned dark-gray and his hair grew and turned dark blue. Additionally, he grew webbed-claw-shaped wings from his back which he could use to glide, and a dark, star-shaped mark appeared across the bridge of his nose. Like all Cursed Seals, the user receives increased chakra levels and physical capabilities when the seal is active.

Anko received her Cursed Seal when she was a student of Orochimaru. She, along with nine others, were the first people to receive a Cursed Seal. She was the only one to survive the application, establishing the one-in-ten success rate for the procedure. Because she lacked the will to use it, her seal receded, and Orochimaru wiped her memory. Orochimaru was able to briefly reactivate the seal when they fought in the Forest of Death before the Third Hokage sealed it off again.

Orochimaru branded Sasuke with the Cursed Seal in the second phase of the Chunin Exams, which took place in the Forest of Death. Orochimaru intended to have the seal corrode Sasuke's mind so that he could become his next body. Kakashi Hatake used the Evil Sealing Method to try and prevent this, but its effectiveness relied on Sasuke's choosing not to use his Cursed Seal. Sasuke ultimately chose to advance his seal to its second level, and went to Orochimaru with the help of the Sound Four. During Sasuke's battle in Part II with Itachi Uchiha, the Cursed Seal, along with Orochimaru (having earlier been absorbed into Sasuke's body), were removed with Susanoo.