Many new HIV-1 infections in the USA occur in injection drug users (IDUs). HIV-1seroconversion of IDUs is mainly associated with injection-related risk factors. Harm- reduction programmes concentrate on injection-risk behaviour. We aimed to establish whether injection or sexual risk factors, or both, were associated with HIV-1antibody seroconversion of street-recruited IDUs in San Francisco, from 1986 to 1998. IDUs were enrolled every 6 months from four community sites. We did a nested case-control study comparing 58 respondents who seroconverted between visits with 1134 controls who remained seronegative. Controls were matched with cases by sex and date. Adjusted odds ratios and 95% CI were calculated for men and women by use of conditional logistic regression. Men who had sex with men were 8.8 times as likely to seroconvert (95% CI 3.7-20.5) as heterosexual men. Women who reported having traded sex for money in the past year were 5.1 times as likely as others to seroconvert (95% CI 1.9-13.7). Women younger than 40 years were more likely to seroconvert than those 40 years or older (2.8 [1.05-7.6]), and women who reported having a steady sex-partner who injected drugs were less likely to seroconvert than other women (0.32 [0.11-0.92]). HIV-1 seroconversion of street-recruited IDUs in San Francisco is strongly associated with sexual behaviour. HIV-1risk might be reduced by incorporation of innovative sexual-risk-reduction strategies into harm-reduction programmes.