BACKGROUND: Cancer survivors are at increased risk for subsequent primary cancers. People living with HIV are at increased risk for AIDS-defining and non-AIDS-defining cancers, but little is known about their risk of first versus second primary cancers. We identified first and second primary cancers that occurred in above population expected numbers among people diagnosed with HIV in San Francisco, and compared first and second cancer incidence across five time periods that corresponded to important advances in antiretroviral therapy. METHODS: In this population-based study, we used the San Francisco HIV/AIDS case registry to identify people aged 16 years and older who were diagnosed with HIV/AIDS in San Francisco (CA, USA) between Jan 1, 1990, and Dec 31, 2010. We computer-matched records from the registry with the California Cancer Registry to identify primary cancers diagnosed between Jan 1, 1985, and Dec 31, 2013. We calculated year, age, sex, and race adjusted standardised incidence ratios with exact 95% CIs and trends in incidence of first and second AIDS-defining and non-AIDS-defining cancers from 1985 to 2013. FINDINGS: Of the 22 623 people diagnosed with HIV between Jan 1, 1990, and Dec 31, 2010, we identified 5655 incident primary cancers. We excluded 48 cancers with invalid cancer sequence numbers and 1062 in-situ anal cancers, leaving 4545 incident primary cancers, comprising 4144 first primary cancers, 372 second primary cancers, 26 third primary cancers, and three fourth or later primary cancers. First primary cancer standardised incidence ratios were elevated for Kaposi sarcoma (127, 95% CI 121-132), non-Hodgkin lymphoma (17·2, 16·1-18·4), invasive cervical cancer (8·0, 4·1-11·9), anal cancer (46·7, 39·7-53·6), vulvar cancer (13·3, 6·1-20·6), Hodgkin's lymphoma (10·4, 8·4-12·5), eye and orbit cancer (4·2, 1·4-6·9), lip cancer (3·8, 1·3-6·2), penile cancer (3·8, 1·4-6·1), liver cancer (3·0, 2·3-3·7), miscellaneous cancer (2·3, 1·7-3·0), testicular cancer (2·0, 1·4-2·6), tongue cancer (1·9, 1·1-2·7), and lung cancer (1·3, 95% CI 1·1-1·6). Second primary cancer risks were increased for Kaposi sarcoma (28·0, 95% CI 20·2-35·9), anal cancer (17·0, 10·2-23·8), non-Hodgkin lymphoma (11·1, 9·3-12·8), Hodgkin's lymphoma (5·4, 1·1-9·7), and liver cancer (3·6, 1·4-5·8). We observed lower first primary cancer standardised incidence ratios for prostate cancer (0·6, 95% CI 0·5-0·7), colon cancer (0·6, 0·4-0·8), and pancreatic cancer (0·6, 0·3-1·0), and lower second primary cancer standardised incidence ratios for testicular cancer (0·3, 0·0-0·9), kidney cancer (0·4, 0·0-0·9), and prostate cancer (0·6, 0·2-0·9). First and second primary AIDS-defining cancer incidence declined, and second primary non-AIDS-defining cancer incidence increased over time. INTERPRETATION: Because of an increased risk for both first and second primary cancers, enhanced cancer prevention, screening, and treatment efforts are needed for people living with HIV both before and after initial cancer diagnosis. FUNDING: University of California San Francisco and US Centers for Disease Control and Prevention.