This investigation highlighted the risk of cancer in 8074 HIV-infected people and in 2875 transplant recipients in Italy and France. Observed and expected numbers of cancer were compared through sex- and age-standardised incidence ratios (SIRs) and 95% confidence intervals (CIs). After 15 years of follow-up, the cumulative probability of cancer was 14.7% in transplant recipients and 13.3% in HIV-positives. The SIRs for all cancers were 9.8 in HIV-positives and 2.2 in transplants. Kaposi’s sarcoma (SIR=451 in HIV-positives, 125 in transplants) and non-Hodgkin lymphoma (SIR=62 and 11.1, respectively) were the most common cancers. A significantly increased SIR for liver cancer also emerged in both groups. The risk of lung cancer was significantly elevated in heart transplant recipients (SIR=2.8), and of borderline statistical significance in HIV-positive people (95% CI:0.9–2.8). Immune depression entails a two-fold increased overall risk of cancers, mainly related to cancers associated with a viral aetiology.