ImportanceComprehensive data for racial and ethnic disparities after second primary cancers (SPCs) are lacking despite the growing burden of SPCs.ObjectiveTo quantify racial and ethnic disparities in survival among persons with SPCs.Design, Setting, and ParticipantsThis population-based, retrospective cohort study used data from 18 Surveillance, Epidemiology, and End Results registries in the US for persons diagnosed with the most common SPCs at age 20 years or older from January 1, 2000, to December 31, 2013 (with follow-up through December 31, 2018). Data were analyzed between January and April 2023.ExposureRace and ethnicity (Hispanic, non-Hispanic Asian or Pacific Islander, non-Hispanic Black, and non-Hispanic White).Main Outcomes and MeasuresThe main outcomes were 5-year relative survival and cause-specific survival. Cause-specific hazard ratios (HRs) were calculated for death from cancer or cardiovascular disease (CVD) in each racial and ethnic minority population compared with the White population overall and stratified by SPC type, with adjustment for sex, year and age at SPC diagnosis, and prior cancer type and stage (baseline model) and additionally for county attributes (household income, urbanicity), SPC characteristics (stage, subtype), and treatment.ResultsAmong 230 370 persons with SPCs (58.4% male), 4.5% were Asian or Pacific Islander, 9.6% were Black, 6.4% were Hispanic, and 79.5% were White. A total of 109 757 cancer-related deaths (47.6%) and 18 283 CVD-related deaths (7.9%) occurred during a median follow-up of 54 months (IQR, 12-93 months). In baseline models, compared with the White population, the risk of cancer-related death overall was higher in the Black (HR, 1.21; 95% CI, 1.18-1.23) and Hispanic (HR, 1.10; 95% CI, 1.07-1.13) populations but lower in the Asian or Pacific Islander population (HR, 0.93; 95% CI, 0.90-0.96). When stratified by 13 SPC types, the risk of cancer-related death was higher for 10 SPCs in the Black population, with the highest HR for uterine cancer (HR, 1.87; 95% CI, 1.63-2.15), and for 7 SPCs in the Hispanic population, most notably for melanoma (HR, 1.46; 95% CI, 1.21-1.76). For CVD-related death, the overall HR was higher in the Black population (HR, 1.41; 95% CI, 1.34-1.49), with elevated risks evident for 11 SPCs, but lower in the Asian or Pacific Islander (HR, 0.75; 95% CI, 0.69-0.81) and Hispanic (HR, 0.90; 95% CI, 0.84-0.96) populations than in the White population. After further adjustments for county attributes and SPC characteristics and treatment, HRs were reduced for cancer-related death and for CVD-related death and associations in the same direction remained.Conclusions and RelevanceIn this cohort study of SPC survivors, the Black population had the highest risk of both death from cancer and death from CVD, and the Hispanic population had a higher risk of death from cancer than the White population. Attenuations in HRs after adjustment for potentially modifiable factors highlight opportunities to reduce survival disparities among persons with multiple primary cancers.