Several lines of evidence suggest that the incidence of anal cancer is increasing in association with the HIV epidemic. Over the last several years, parallel studies in San Francisco and Seattle examining the prevalence, development and natural history of anal cancer precursor lesions have shown that such lesions (termed anal intraepithelial neoplasia or AIN) are very common among all homosexual men but particularly among those with HIV infection. High grade AIN (HGAIN), the lesion thought to be most closely associated with anal cancer, was detected in 6% of men with HIV infection, compared to 1.5% of seronegative men. Anal and cervical cancer share much in common, as do their precursor lesions, AIN and cervical intraepithelial neoplasia (CIN). Treatment of CIN has proven to be instrumental in reducing the rates of invasive cervical cancer, and similarly, we believe that effective therapy for AIN will be necessary to reduce the incidence of invasive anal cancer. Little is known about the most effective methods of treating HGAIN, but primary ablative therapy is the standard approach at this time. there is concern about this approach due to high recurrence rates seen in the small number of men followed to date, as well as preliminary data among HIV-positive women showing that a high percentage of CIN lesions recur after primary ablative therapy. We are therefore proposing a collaborative phase I-II trial based at UCSF and the University of Washington of adjunctive therapy to be given after primary ablative therapy. This therapy will consist of isotretinoin or a combination of isotretinoin and interferon-alpha. This trial will: 1) determine the maximum tolerated dose of isotretinoin and 2) evaluate the efficacy of primary ablation alone, or ablation plus adjunctive therapy in preventing recurrent of AIN. Subjects for this trial will be recruited from among those men enrolled in our ongoing studies. Up to 21 subjects at each site will be enrolled in a dose escalation study to establish the appropriate dose of isotretinoin with and without interferon-alpha, with all subjects enrolled in Seattle having CD4 counts above 300 and all subjects in San Francisco having CD4 counts below 300. After the maximally tolerated dose has been established, 39 men at each study site who have developed HGAIN will be randomized into one of three groups: primary ablative therapy alone; primary ablative therapy plus isotretinoin; or primary ablative therapy plus the combination of isotretinoin and interferon- alpha. Each subject will be followed for one year with anoscopy, anal cytology and anal biopsies to determine the AIN recurrence rates, and the effects of these treatment modalities on human papillomavirus DNA levels will be assessed. Subjects will be carefully monitored for drug toxicity and immune status. We believe that data generated by this trial will be of great value in designing Phase III trials. Ultimately, data from this trial will be useful in prevention of anal cancer in HIV-positive men, as well as designing trials for prevention of cervical cancer in HIV- positive women.