Cancer survivors are at excess risk of developing second primary cancers, but the precise level of risk in Japanese patients is not known. To investigate the risk of survivors developing second primary cancers, we conducted a retrospective cohort study using data from the Osaka Cancer Registry. The study subjects comprised all reported patients aged 0-79 years who were first diagnosed with cancer between 1985 and 2004 in Osaka and who survived for at least 3 months, followed-up through to December 2005. A metachronous second primary cancer was defined as any invasive second cancer that was diagnosed between 3 months and 10 years after the first cancer diagnosis. The main outcome measures were incidence rates per 100,000 person-years, cumulative risk and standardized incidence ratios (SIR) of second primary cancer. Metachronous second primary cancers developed in 13,385 of 355,966 survivors (3.8%) after a median follow-up of 2.5 years. Sex-specific incidence rates of metachronous second primary cancer per 100,000 person-years increased with age, and were higher among men than women (except for the 0-49 years age group), but these rates did not differ over the study period. The 10-year cumulative risk was estimated as 13.0% for those who first developed cancer at 60-69 years of age (16.2% for men, 8.6% for women). The SIR among those with first cancer diagnosed at 0-39 and 40-49 years of age were 2.13 and 1.52, respectively, in both sexes, whereas the SIR among cancers of the mouth/pharynx, esophagus and larynx were much higher than one as for site relationships. We showed that cancer survivors in Osaka, Japan, were at higher risk of second primary cancers compared with the general population. Our findings indicate that second primary cancers should be considered as a commonly encountered major medical problem. Further investigations are required to advance our understanding to enable the development of effective measures against multiple primary cancers.