||Data from epidemiologic and twin studies suggest an important role of genetic susceptibility in prostate cancer. Variants of the macrophage scavenger receptor 1 (MSR1) gene have been linked to both hereditary and sporadic prostate cancer, although the evidence is inconclusive. Most studies have been conducted on Caucasians. The role of MSR1 in prostate cancer development among Asians, for whom rates of prostate cancer are low but rising rapidly, is unclear. To evaluate further the relationship between MSR1 variants and prostate cancer risk, we sequenced all the 11 MSR1 exons, exon-intron junctions, promoter regions, as well as 5' and 3' untranslated regions (UTRs) in 86 individuals from Shanghai, China. We identified a total of 21 sequence variants, including three novel variants that have not been reported previously. To balance genotyping cost and the capacity to capture sufficient genetic variation, we genotyped four haplotype-tagging variants (P275A, INDEL7, P346P and 3' UTR 70006), which capture 85% of the genetic variation in MSR1 in this population. These four variants, plus two other variants (PRO3 and INDEL1) that have been linked to prostate cancer risk in the previous studies, were typed for all study subjects, which included 130 prostate cancer cases, 130 patients with benign prostatic hyperplasia and 150 controls randomly selected from the population. Three of the six variants were associated with prostate cancer. Men with a P346P (a novel variant) G allele (AG + GG) had a significantly reduced risk of total prostate cancer [odds ratio = 0.47, 95% confidence interval (CI) 0.23-0.96], whereas those with a P275A G allele had a 37% reduced risk of prostate cancer (95% CI 0.39-1.02), with more pronounced reduction in risk seen for localized cancer cases (odds ratio = 0.25, 95% CI 0.12-0.52; P = 0.001). In addition, men with the INDEL7 variant had a 67% reduced risk of localized cancer (95% CI 0.16-0.68). Based on the four tagging variants, we inferred four major haplotypes that accounted for >90% of the haplotype variation in this population. The haplotype frequencies were significantly different between localized prostate cancer cases and controls, with a global P value of 0.004, and the haplotype containing the minor alleles of the P275A and INDEL7 variants was associated with a significantly reduced risk of localized prostate cancer (odds ratio = 0.28, 95% CI 0.13-0.59), relative to the most common haplotype. These results, although modest and confined mainly to localized prostate cancer, suggest that MSR1 polymorphisms may play a role in prostate cancer etiology in Chinese men. The role of MSR1 warrants further investigation in larger studies and other populations.