Several CC-motif chemokine ligands (CCLs) can block HIV-1-binding sites on CC-motif chemokine receptor 5 (CCR5) and inhibit viral entry. We studied single-nucleotide polymorphisms (SNPs) in genes encoding three CCR5 ligands (CCL3 (MIP-1α), CCL4 (MIP-1Β) and CCL5 (RANTES)) along with an adjacent gene encoding a CCR2 ligand (CCL2 (MCP-1)) to identify candidate markers for HIV-1 infection and pathogenesis. Analyses of 567 HIV-1 serodiscordant Zambian couples revealed that rs5029410C (in CCL3 intron 3) was associated with lower viral load (VL) in seroconverters, adjusted for gender and age (regression Β0.57 log 10, P4 × 10-6). In addition, rs34171309A in CCL3 exon 3 was associated with increased risk of HIV-1 acquisition in exposed seronegatives (hazard ratio1.52, P0.006 when adjusted for VL of the initially seropositive partner and genital ulcer/inflammation). SNP rs34171309 encodes a conservative Glu-to-Asp substitution. Five neighboring SNPs in tight linkage disequilibrium with rs34171309 all showed similar associations with HIV-1 acquisition. How these multiple CCL3 SNPs may alter the occurrence or course of HIV-1 infection remains to be determined. © 2012 Macmillan Publishers Limited All rights reserved.