Data collected from eleven Italian population-based cancer registries (overall population 7,200,000 inhabitants) were used to compute the incidence of second independent cancers (MP) in a cohort of cancer patients aged 15 years or more. Overall, 240111 patients have been followed for 544438 person-years during which 8766 second primary cancers were diagnosed leading to an observed to expected ratio (SIR) of MP of 1.08 (95% Confidence Interval (CI): 1.05-1.12). Restricting the analysis to metachronous cancers, there were 6974 second primary cancers diagnosed among 198303 patients during 508,648 person-years with an SIR of 0.93 (95% CI: 0.90-0.96). According to the time since first cancer diagnosis, the SIR was significantly higher than expected during the first 2 months, then the overall risk was slightly lower than 1 up to 10 years after diagnosis. No differences were observed according to gender. The SIR significantly differed among the age groups with consistent excess risks in subjects younger than 65 years in comparison with older ones. Overall, significantly elevated SIR for metachronous cancers were evidenced for oral cavity and pharynx, larynx, connective, skin non-melanoma, ovary and kidney cancers. For each cancer site, the site-specific risk of further MP has been evaluated. The identification of strong site-specific associations may be useful for clinicians when following-up patients.