Aim: To evaluate the safety of rechallenge with a different anti-PD-1 antibody after an immune-related adverse event (irAE) that has prompted the discontinuation of anti-PD-1 therapy. Patients & methods: We describe two patients with metastatic melanoma who developed potentially disabling and early irAEs following anti-PD-1 treatment. Therapy was discontinued and toxicities resolved with corticosteroids. Results: Rechallenge switching to an alternative anti-PD-1 antibody did not lead to a new or recurrent irAE. Conclusion: Switching to a different anti-PD-1 antibody when resuming therapy after an irAE might be a safe strategy and warrants further investigation. Structural and biological differences between antibodies might explain the different safety outcomes.