One hundred and twenty Danish homosexual men were enrolled to characterize risk factors for anal type-specific human papillomavirus (HPV) expression and to examine its association with anal epithelial atypia. Detection of HPV strongly correlated with immunosuppression measured by Tlymphocyte subset markers and rose nearly linearly from 7.3% among subjects with CD4/CD8 ratios above 1.0 to 35.3% among those with a ratio below 0.4 (p trend = 0.003). No association was found between presence of HPV and a wide range of lifestyle factors including number of sex partners/year, smoking, alcohol consumption and illegal drug intake. However, self-reported history of anal condyloma in the past year was correlated with HPV (p < 0.001). Simultaneous testing for presence of HPV in the oral cavity showed evidence of HPV 16, 18 and 31, 33, 35. Anal smears were abnormal in 19.5% of the men and correlated strongly with presence of HPV (OR = 601, p < 0.0001). Type-specific associations were found with HPV 31/33/35 (OR = 8.5) and HPV 16/18 (OR = 3.1) only. The association remained significant after adjusting for immune status. Overall, HPV was detected in 50% of the cases with abnormal smears. However, HPV was found in all subjects with abnormal smears and a CD4/CD8 ratio below 0.4, compared to only 3 of 14 subjects with abnormal smears and a ratio ± 1.3. In conclusion, (I) HPV may be missed in a substantial number of infected subjects with a normal immune system. This may have an impact on studies trying to describe risk factors for HPV transmission and its correlation with cancer development. (2) The finding of HPV 16,18 and 31,33,35 in the oral cavity makes oral-genital sexual activity at least a hypothetical route of transmission for these HPV types. (3) HPV appears to play a central role in the development of anal epithelial abnormality.