Aim: The molecular mechanisms involved in progression of squamous cell carcinoma of the anus (SCCA) are poorly elucidated, as well as the potential role of HIV infection. Loss of heterozygosity (LOH) is one of the mechanisms responsible for inactivation of tumor suppressor genes (TSG). We hypothesized that HIV-induced immunosuppression may contribute to an alternate molecular pathway in SCCA progression. This study was undertaken to compare the molecular biology of SCCA in HIV positive and HIV negative patients. Methods: We retrieved tumor specimen from 18 HIV negative and 10 HIV positive patients, diagnosed with SCCA in two institutions. DNA from tumor and normal tissues was extracted, and then amplified by PCR. LOH patterns were investigated with 14 primers at 6 loci: 18q (DCC); 13q (Rb); 17p (p53); 11q; 2q; and 5q (APC). LOH was defined by a tumor DNA/normal tissue DNA >2. Results: HIV positive patients were younger (36± 7 Vs. 53±13 years, p=0.001) and showed a trend towards tumors of larger size (3.7±1.6 Vs. 2.6±1.5 cm, p=0.09). A total of 46 allelic losses were observed in the whole group. LOH were the most frequent on chromosome 11q (13 out of 28 patients (46%)). When considering all loci, tumors in HIV negative patients were more likely to present with LOH than tumors in HIV positive patients (38 LOH/108 loci (35.2%) vs. 8 LOH/60 loci (13.3%), p=0.002). Differences between the two groups with regard to allelic losses were also observed at specific loci, such as 18q (7/18 (HIV-) vs. 0/10 (HIV+), p=0.03) and 17p (8/18 (HIV-) vs. 1/10 (HIV+), p=0.09). Conclusion: Consistent LOH on chromosomes 17p, 18q and 11q were observed in HIV negative patients with SCCA. By contrast, allelic losses at 17p and 18q seem to be rare in tumors of HIV positive individuals. These data suggest that immunosuppression may promote SCCA progression through an alternate pathway, and that persistence of human papillomavirus within the anal canal may play a central role in this process.