Type I interferon (IFN) signalling is involved in the antitumour immune response in patients with melanoma. The combination of pegylated (PEG)-IFNα2b with the anti-PD-1 antibody pembrolizumab was tested in a phase Ib/II trial involving 43 patients with stage IV melanoma. At a median follow-up duration of 25 months, the objective response rate was 60.5% and 46.5% of patients had ongoing responses. The median progression-free survival duration was 11.0 months in the whole cohort and not reached in patients with a response. The median overall survival duration was not reached. Grade 3–4 treatment-related adverse events (AEs) occurred in 48.8% of patients and immune-related AEs of any grade in 34.9% of patients. No treatment-related deaths were observed. Results from large-cohort randomized trials are needed to further determine the potential clinical benefit of adding IFNα to immune-checkpoint inhibitors.