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Background: Over recent years, immune checkpoint inhibitors (ICIs) have changed the clinical management and prognosis for most cancers. However, data on older patients in clinical trials are scarce. Objective: We performed a systematic review and pooled analysis of real-life studies to explore the efficacy and toxicity of ICIs in unselected older individuals in multiple tumor settings treated outside of clinical trials. Patients and Methods: We searched articles, including prospective cohort studies, observational or retrospective series, or expanded access programs, published in English from 2010 to October 2020 in PubMed, MEDLINE, the Cochrane Library, and EMBASE. We excluded hematological malignancies. Results: Forty-eight studies met the predefined criteria and were eligible for inclusion in the systematic review. We included 5524 patients. The pooled median overall survival was 8.9 (95% CI 7.3–10.5) and 14.3 (95% CI 11.3–17) months for non-small cell lung cancer (NSCLC: n = 17 studies; 95% in pretreated setting) and melanoma, respectively (n = 3). Median progression-free survival was 3.2 (95% CI 2.7–3.8) and 7.9 (95% CI 6.05–9.78) months for NSCLC and melanoma cohorts. Pooled rates of Grade 1–5 hepatitis, pneumonitis, hypothyroidism, and diarrhea were 5.3% (95% CI 3.7–7.6), 6% (95% CI 3.8–9.4), 8.3% (95% CI 5.4–12.5) and 7.6% (95% CI 5.7–10), respectively. Conclusions: Our findings suggest that ICIs could be safely administered in older individuals with comparable survival outcomes with respect to younger individuals. Future studies should include some form of geriatric assessment to improve patient stratification. [ABSTRACT FROM AUTHOR]