Nitrous oxide (N₂O) is a widely used anesthetic agent. We report two patients with sickle cell disease (SCD) who presented with complications following the use of N₂O. Patient 1, a 15-year-old girl, presented severe hyperhomocysteinemia, pancytopenia, vitamin B₁₂ deficiency, and peripheral polyneuropathy after massive use of N₂O for pain management. At the 1-year follow-up, hyperhomocysteinemia and B₁₂ deficiency had resolved, but she had persisting mild symptoms of polyneuropathy. Patient 2, a 17-year-old boy, presented only severe hyperhomocysteinemia, only partially corrected by initial B₁₂ supplementation. Careful monitoring of N₂O use, especially in patients with SCD, is mandatory to prevent complications.