Treatment of advanced melanoma with combined PD-1/CTLA-4 blockade commonly causes serious immune-mediated complications. Here, we identify a subset of patients predisposed to immune checkpoint blockade-related hepatitis who are distinguished by chronic expansion of effector memory CD4(+) T cells (T-EM cells). Pre-therapy CD4(+) T-EM cell expansion occurs primarily during autumn or winter in patients with metastatic disease and high cytomegalovirus (CMV)-specific serum antibody titres. These clinical features implicate metastasis-dependent, compartmentalised CMV reactivation as the cause of CD4(+) T-EM expansion. Pre-therapy CD4(+) T-EM expansion predicts hepatitis in CMV-seropositive patients, opening possibilities for avoidance or prevention. 3 of 4 patients with pre-treatment CD4(+) T-EM expansion who received alpha PD-1 monotherapy instead of alpha PD-1/alpha CTLA-4 therapy remained hepatitis-free. 4 of 4 patients with baseline CD4(+) T-EM expansion given prophylactic valganciclovir and alpha PD-1/alpha CTLA-4 therapy remained hepatitis-free. Our findings exemplify how pathogen exposure can shape clinical reactions after cancer therapy and how this insight leads to therapeutic innovations. Checkpoint blocking therapies are used to treat metastatic melanoma, but can have adverse immune-mediated effects, including liver pathology. Here the authors identify an expanded pool of CD4(+) effector memory T cells resulting from prior CMV exposure as a risk factor for this adverse effect in these patients.