ABSTRACT: Polymorphisms in Toll-like receptor (TLR) and human ?-defensin (hBD, encoded by DEFB) genes have been evaluated for their associations with HIV infection and disease outcomes. Those studies, conducted in various populations under a variety of study designs, generally revealed that specific single nucleotide polymorphisms (SNPs) in TLR1, 2, 3, 4, 6, 7, 8, and 9 genes, and copy number variation (CNV) in DEFB4 (encoding hBD-2), DEFB103A (encoding hBD-3), and DEFB104A (encoding hBD-4) genes are among potential genetic factors that can affect susceptibility to HIV infection and/or disease progression. The information regarding their prevalence in Papua New Guinea (PNG) is very limited for TLR SNPs, and not available for DEFB CNV. The present study provides a preliminary assessment of these genetic polymorphisms in samples collected from the Wosera (East Sepik Province, n = 29) and Liksul (Madang Province, n = 23) areas. Wosera samples were analyzed for a total of 41 SNPs in 8 TLR genes (TLR1, 2, 3, 4, 6, 7, 8, and 9), and both sample sets were analyzed for CNV in DEFB4/103A/104A genes. A number of TLR SNPs were not detected, and many other SNPs were present at low frequencies (minor allele frequencies ?0.05) in the Wosera samples. The DEFB4/103A/104A copy numbers were significantly different between the two sample sets (p = 0.024). Validation of these results, using larger sample sizes as well as samples from other areas of PNG, is warranted. In addition, genetic association studies are needed to estimate the effects of these polymorphisms on HIV infection and disease progression in PNG.