Background: The relative risk of developing a second tumor by site of primary tumor or gender is still unclear. Methods: We retrospectively analyzed data of 24,224 consecutive patients admitted to the European Institute of Oncology between 2000 and 2006 for a first primary invasive tumor. All the data were extracted from the institutional Tumor Registry. All tumors were registered and indexed within the same patient’s record. We limited the analysis to the patients who were diagnosed and received at least one treatment in IEO for their first primary tumor. Follow-up was based on the last registered patient’s control visit. Cumulative incidence was compared across different subgroups by means of the Gray test. The observed cases of second metachronous primary tumors was compared with the number of cancers we expected from the general Italian population. We used the standardized incidence ratio (SIR), defined as the ratio of the number of second cancers observed to the number of second cancers expected, to estimate the relative risk of second cancers, and we calculated 95% confidence intervals (95% CIs) by applying the Wilson and Hilferty approximation for chi-square percentiles. Results: In this population the 5-year cumulative incidence of a second tumor on the average population was 5.0%, SIR (CI 95%) was 1.3 (1.2-1.4). The Table reports details on observed versus expected second metachronous primary tumors by first tumor site. Conclusions: Cancer patients have a higher risk of a second primary tumor than general population.