Classic Kaposi's sarcoma (CKS) is a multifocal vascular mesenchymal tumour of unknown origin. Human herpesvirus 8 (HHV8) is now considered to be strongly involved, as a necessary co-factor, though insufficient for development of the disease. Additional identified risk factors include environmental factors, personal habits and genetic susceptibility, with different loci suspected of being risk factors for CKS. Since various human leukocyte antigen (HLA) patterns have been suggested as potential host-related co-factors, the distribution of these alleles was studied in 41 CKS patients, 285 geographically-matched healthy controls (HC) and 17 HHV8-positive controls. Molecular typing of HLA was performed using the polymerase chain reaction sequence-specific primer method (SSP-PCR). Frequency distribution was evaluated by the Chi-squared test with Yates' correction. Odds ratios (OR) and respective 95% confidence limits (CI) were calculated. A significantly higher frequency of HLA-DRB1*13 was observed among the CKS patients (20.7%) compared to the HC (9.8%) (p<0.01; OR: 2.32; 95%CI: 1.21-4.41). Overall, these results indicated that HLA-DRB1*13 may play a role in the development of CKS, while HLA-DQB1*0604 allele involvement occurs in linkage disequilibrium with HLA-DRB1*13. To our knowledge, this is the first study documenting an HLA-DRB1 and -DQB1 loci association with CKS development in the mainland Italian population.