Earlier studies indicate that high circulating levels of insulin-like growth factor-1 (IGF-1) may be associated with premenopausal breast cancer. We studied variations in the IGF-1 gene and the growth hormone (GH1) gene in relation to risk of breast cancer in 667 Ashkenazi Jewish women (321 cases, 346 controls) from a population-based case-control study in Northern Israel, and a clinical series of 331 founder BRCA mutation carriers (161 affected, 170 unaffected). All participants were tested for six polymorphisms in the IGF-1 gene and one GH1 polymorphism. Logistic regression models were used to estimate odds ratios for haplotype-specific and genotype-specific age-adjusted risks. Two common IGF-1 haplotypes (ATTCAC, GAGTGT) were found, when compared with the most prevalent haplotype ATTCGC (32.5%), to be associated with a decreased risk of breast cancer in premenopausal noncarrier women only. Age-adjusted odds ratios were 0.5 (95% confidence interval: 0.28-0.92) for ATTCAC and 0.46 (95% confidence interval: 0.24-0.89) for GAGTGT. The GH1 polymorphism did not influence the risk of breast cancer in our study population. The IGF-1 gene seems to be associated with breast cancer risk in premenopausal Ashkenazi Jewish women who are not carriers of mutations in BRCA1/2 genes.