We sought to determine whether hairy leukoplakia (HL), an Epstein-Barr virus-related oral lesion, is associated with receptive oral sex activity and cigarette smoking among HIV-positive gay men. Oral examinations were conducted every 6 months among San Francisco Men's Health Study participants over a 6-year period. We fitted time-to-lesion regression models to compare the incidence of HL among men who had mouth-to-penis contact with various numbers of partners, while controlling for cigarette smoking and CD4 count. The 6-year incidence of HL was 32% among 291 HIV-positive men. We found no significant increase in the hazard of developing HL for each additional insertive-oral-sex male partner in the past 6 months (relative hazard = 1.01; 95% confidence interval [CI], 0.99, 1.02), and a similar lack of association when number of sex partners was categorized. However, the hazard of developing HL doubled with any 300-unit decrease in CD4 count (95% CI, 1.4, 2.7), or if men smoked > or =20 cigarettes/day compared with nonsmokers (95% CI, 1.2, 3.9). This finding, which may suggest one effect that smoking produces on the oral mucosa's local immune response, merits further investigation.