Human T-lymphotropic virus-I (HTLV-I) causes adult T-cell leukemia/lymphoma (ATL) and HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP). We postulated a higher disease risk for people with common human leukocyte antigen (HLA) types, due to a narrower immune response against viral or neoplastic antigens, compared to people with uncommon types. HLA class-I (A,B) and class-II (DRB1, DQB1) allele and haplotype frequencies in 56 ATL patients, 59 HAM/TSP patients and 190 population-based, asymptomatic HTLV-I-infected carriers were compared by logistic regression overall (score test) and with odds ratios (ORs) for common types (prevalence >50% of asymptomatic carriers) and by prevalence quartile. HTLV-I proviral load between asymptomatic carriers with common versus uncommon types was compared by t-test. ATL differed from asymptomatic carriers in overall DQB1 allele and class-I haplotype frequencies (p ≤≤ 0.04). ATL risk was increased significantly with common HLA-B (OR 2.25, 95% CI 1.19–4.25) and DRB1 (OR 2.11, 95% CI 1.13–3.40) alleles. Higher prevalence HLA-B alleles were associated with higher ATL risk (OR 1.14 per quartile, ptrend = 0.02). Asymptomatic carriers with common HLA-B alleles had marginally higher HTLV-I proviral load (p = 0.057). HAM/TSP risk did not differ consistently with common HLA types. Thus, ATL risk, but not HAM/TSP risk, was increased with higher prevalence HLA-B alleles. Perhaps breadth of cellular immunity affects risk of this viral leukemia/lymphoma. © 2007 Wiley-Liss, Inc.