Purpose: History of keratinocyte carcinoma (KC) has been associated with survival following the diagnosis of a second primary malignancy (SPM), with the direction of the association varying by cancer type. Research is needed to elucidate the role of other key factors in this association. Methods: A retrospective cohort study was conducted among patients newly diagnosed and/or treated at Moffitt Cancer Center in December 2008–April 2020 with breast cancer, lung cancer, melanoma, colon cancer, prostate cancer, and non-Hodgkin lymphoma/chronic lymphocytic leukemia (NHL/CLL) (n = 29,156). History of KC was obtained from new patient intake questionnaires. Age- and stage-adjusted hazard ratios (HR) and 95% confidence intervals (CI) were calculated to estimate the association between history of KC and survival following each cancer, stratified by demographic/clinical characteristics. Results: KC history was most prevalent in patients with melanoma (28.7%), CLL (19.8%) and lung cancer (16.1%). KC history was associated with better overall survival following prostate cancer (HR = 0.74, 95% CI = 0.55–0.99) and poorer overall survival following CLL (HR = 1.73, 95% CI = 1.10–2.71). Patients with a history of KC experienced better survival within the first four years of a melanoma diagnosis (HR = 0.79, 95% CI = 0.67–0.92); whereas poorer survival was observed for patients who survived 7 + years after a melanoma diagnosis (HR = 2.18, 95% CI = 1.17–4.05). Stratification by treatment and stage revealed directional differences in the associations between KC history and survival among patients with breast cancer and melanoma. Conclusions: KC history may be a predictor of survival following an SPM, possibly serving as a marker of immune function and/or DNA damage repair capacity. [ABSTRACT FROM AUTHOR]