Anal cancer incidence appears to be increasing in association with the HIV epidemic. Parallel studies in San Francisco and Seattle of the prevalence, development and natural history of anal cancer precursor lesions have shown that these lesions (anal intraepithelial neoplasia or AIN) are very common among homosexual men but particularly among HIV seropositive (HIV+) men. We have detected high grade AIN (HGAIN), the lesion thought to be most closely associated with development of subsequent anal cancer, in 6% of HIV+ men; furthermore, HIV+ men are more likely to develop HGAIN than are HIV seronegative (HIV-) men. Anal and cervical cancer share much in common, as do their precursor lesions (AIN and cervical neoplasia (CIN)). Treatment of CIN has successfully reduced the rates of invasive cervical cancer, and we believe that effective therapy for AIN will have a similar effect on the incidence of invasive anal cancer. Primary ablative therapy is considered the standard treatment for AIN, although this has not been systematically evaluated. It is also likely that ablative therapy in HIV+ subjects results in high recurrence rates of anal disease, based on very limited data in men and preliminary data indicating high CIN recurrence rates among HIV+ women. We are proposing a collaborative phase I-II trial of isotretinoin or a combination of isotretinoin and interferon-alpha (IFN) as an adjunct to primary ablative therapy, to be based at UCSF and the University of Washington. The aims are to: 1) determine the maximum tolerated dose (MTD) of isotretinoin with and without IFN (Phase I), and 2) evaluate the efficacy of primary ablation alone, or ablation plus adjunctive chemotherapy in preventing recurrence of AIN (Phase II). Subjects will be recruited from among HIV+ men enrolled in ongoing studies of anal neoplasia at the two clinical sites. Up to 21 subjects at each site will be enrolled in the phase I study; subjects enrolled in Seattle will have CD4 counts above 300, subjects enrolled at San Francisco will have CD4 counts below 300. The phase II study will enroll 39 men with HGAIN who will be randomized into one of three groups: primary ablative therapy alone; primary ablative therapy plus isotretinoin; or primary ablative therapy plus isotretinoin and IFN. Each subject will be carefully monitored for drug toxicity and will be followed for one year to determine AIN recurrence rates and the effect of treatment on human papillomavirus DNA levels. This data will be important for the design of future Phase III trials, and ultimately, will be potentially useful in developing strategies for preventing squamous cell carcinoma among HIV infected men and women.