Background: Immune checkpoint inhibitors (ICIs) have improved prospects for some, but not all patients with cancer and frequently induce severe immune-related adverse events (irAEs). While physical activity (PA) has been associated with prolonged survival and diminished toxicity of chemotherapy, its association with ICI efficacy and toxicity is currently unknown. Hence, here we study the association between PA in patients undergoing ICI, and survival and severe irAE occurrence. Methods: Patients with advanced cancer receiving anti-PD-(L)1 based immunotherapy at our academic center were enrolled in the UNICIT cohort. All participants who completed the PA questionnaire (SQUASH) at ICI initiation between 10-2019 and 01-2022 were included in this study. PA was quantified by calculating Metabolic Equivalent Task (MET) hours per week and moderate to vigorous sport and leisure time activity. Association of PA with overall survival (OS) was assessed using Cox proportional hazard regression. Association of PA with occurrence of a severe irAE (grade 3 or higher) within one year was assessed using logistic regression in patients with at least one year follow-up. All analyses were adjusted for sex, age, tumor type, treatment intent and ICI type. Results: In total, 251 patients were included, with a median follow-up of 20 months and a median age of 64 years. The majority (153 patients) had melanoma. Median OS was not reached. Compared to low levels of total PA, intermediate and high levels of total MET-hours were associated with prolonged survival (adjusted hazard ratios: 0.56 (95%CI 0.31-1.02) and 0.47 (95%CI 0.26-0.86), respectively; table). Thirty eight out of 209 patients with at least one year of follow-up developed severe irAEs within the first year. Compared to patients with low total PA levels, patients with intermediate or high levels of total PA have a lower odds of developing severe irAEs (adjusted odds ratios: 0.35 (95%CI 0.12-0.90) and 0.19 (95%CI 0.06-0.56), respectively). Similar trends of prolonged OS and reduced odds of severe irAE occurrence were observed in patients who performed more moderate to vigorous sport and leisure time activity. Conclusions: Higher physical activity levels at start of ICI treatment are associated with prolonged survival and lower risk of severe irAEs. Future research needs to elucidate whether inactive patients benefit from increasing PA levels after diagnosis.