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Background: The development of immunotherapy checkpoint inhibitors (ICIs) has revolutionized cancer care. However, old patients are underrepresented in most clinical trials, although they represent a significant proportion of real-world patients. We aimed to evaluate the effectiveness and safety of ICIs in patients older than the age of 70. Methods: We performed a retrospective chart review of 145 patients aged 70 or older treated with ICIs for metastatic or unresectable cancer. Results: Median progression-free survival (PFS) was 10.4 months (95% CI 8.6–13.7), with no differences between octogenarians and septuagenarians (p = 0.41). Female gender (p = 0.04) and first-line treatment setting (p < 0.0001) were associated with a longer median PFS. Median overall survival (OS) was 20.7 months (95% CI 13.5–35.0 months), with no difference based on performance status, cancer site, gender, or between septuagenarians and octogenarians (all p > 0.005). Patients treated with ICIs in the first-line setting reported longer OS compared to treatment in the second-line setting (p < 0.001). Discontinuation of ICIs due to adverse effects was associated with both shorter PFS (p = 0.0005) and OS (p < 0.0001). Conclusion: The effectiveness of ICIs in older cancer patients primarily depends on the line of treatment and treatment discontinuation. Octogenarians experienced similar treatment responses, PFS, OS, and adverse effects compared to septuagenarians. [ABSTRACT FROM AUTHOR]