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Cancer is among the major causes of death after heart transplant (HTx). Risk factors for cancer occurrence in this setting are not well established. This was a retrospective observational study of patients who underwent HTx between 2006 and 2019 and were followed up until May 2024. Clinical variables possibly associated with cancer were assessed with univariable and multivariable analyses. Survival analysis was carried out drawing Kaplan Meier curves and a Cox regression with time-varying covariates were performed to overcome the immortal-time-bias. Three-hundred-thirty-five HTx recipients were included, of whom 42 (12.5%) developed cancer after a median of 6.3 years. In univariable analysis, older age at HTx, smoking history, alcohol use, male sex, ischemic heart disease before HTx, use of cyclosporine rather than tacrolimus, and increased length of follow-up were associated with cancer. Upon multivariable analysis, ischemic heart disease (OR 2.70 [1.19-6.11], p = 0.017) and length of follow-up (OR 1.02 [1.00-1.04], p = 0.007) were independently associated with cancer occurrence. Cox regression revealed a higher risk of mortality among patients with cancer (HR 3.400, [2.026-5.709], p < 0.001). HTx recipients with prior ischemic cardiomyopathy and a longer survival time after transplant show a higher risk of developing cancer. Cancer significantly impairs post-transplant survival.