The relationship between use of recreational drugs and high-risk (HIV-transmitting) homosexual behavior was examined in the Multicenter AIDS Cohort Study (MACS) population. Among the 3916 men who completed both the baseline (1984) and first 6-month follow-up evaluations and were sexually active during the 6 months prior to enrollment, self-reported use of each of 10 classes of recreational drugs in conjunction with sexual activity was analyzed for both cross-sectional and prospective relationships with pattern of sexual behavior using a four-level sexual risk behavior index. At baseline, the proportion of men in the highest risk category (unprotected anal exposures with multiple partners) increased from 36 to 85% when men not using any drugs to men using three or more drugs plus volatile nitrites were examined. In multivariate logistical analyses, volatile nitrite use was significantly associated with failure to maintain or attain lower sexual risk levels after controlling for the effects of age, educational level and numbers of high-risk partners. These results suggest that volatile nitrite use may play an important role in the association between recreational drug use and high-risk sexual behavior among homosexual/bisexual men.