To characterize a host polygenic profile associated with susceptibility to human T lymphotropic virus type I (HTLV-I) infection, we examined common variants in 11 immune-related genes among Jamaican children born to HTLV-I-seropositive mothers. Compared with HTLV-I seronegatives, haplotypes of IL6 (-660G/-635C/-236G) and IL10 (-6653C/-1116G) were significantly associated with HTLV-I infection in children independent of maternal provirus load and duration of breast-feeding (odds ratio [OR], 4.5 [95% confidence interval {CI}, 1.2-17.6], and OR, 3.5 [95% CI, 1.4-9.0], respectively). Our findings are the first, to our knowledge, to suggest that host variation in both proinflammatory and anti-inflammatory genes could influence susceptibility to HTLV-I infection.