Abstract HSD17B1 is an important candidate gene in breast cancer via its role in converting estrone to estradiol. A nonsynonymous G-to-A transition (rs605059) and an intronic C-to-A (rs676387) single-nucleotide polymorphism, which captured most common variation in HSD17B1, were evaluated in several breast cancer studies with inconclusive results. We followed up these findings in the Polish Breast Cancer Study (1,995 cases; 2,296 controls) and the British Studies of Epidemiology and Risk Factors in Cancer Heredity study (4,470 cases; 4,560 controls). Meta-analyses of published data and our own were also conducted among Caucasian women. Consistent with previous reports, we found little to no association with overall risk for heterozygotes and minor allele homozygotes compared with major allele homozygotes for rs605059 [summary odds ratios (95% confidence intervals), 0.93 (0.87-0.99) for GA and 0.96 (0.85-1.08), based on 11,762 cases and 14,329 controls from 10 studies] and for rs676387 [summary odds ratios (95% confidence intervals), 1.04 (0.97-1.12) and 1.12 (0.99-1.27), based on analyses of 11,074 cases and 13,605 controls from 8 studies]. Data from the Polish [n = 586 estrogen receptor–negative (ER-) cases] and British (n = 407) studies did not support the previous findings that ER- tumors were inversely associated with rs676387 AA genotype and positively associated with rs605059 GG genotype, based on subanalyses in 5 prospective cohorts with 354 ER- cases. In conclusion, it is unlikely that common genetic variation in HSD17B1 is associated with a moderate modulation in breast cancer risk overall; however, we cannot exclude the possibility of a very weak effect. Associations between HSD17B1 genotypes and risk for ER- breast cancer were inconsistent across studies and should be studied further. (Cancer Epidemiol Biomarkers Prev 2008;17(10):2766–72)