Insulin-like growth factor (IGF)-1 and interleukin (IL)-6 promote the proliferation and survival of multiple myeloma cells. Variation in genes related to IGF-1 and IL-6 signaling may influence susceptibility to multiple myeloma. To assess their etiologic role, we examined the association of 70 tagging single nucleotide polymorphisms (SNP) in seven IGF-1 and three IL-6 pathway genes with multiple myeloma risk in two prospective cohorts, the Nurses' Health Study and the Health Professionals Follow-up Study. Among the participants who provided DNA specimens, we identified 58 women and 24 men with multiple myeloma and matched two controls per case. We used multivariable logistic regression models to assess the association of the SNPs or tagged haplotypes with multiple myeloma risk. Several SNPs had suggestive associations with multiple myeloma based on large odds ratios (OR), although the corresponding omnibus P values were not more than nominally significant (i.e., at P < 0.05). These SNPs included rs1801278 in the gene encoding insulin receptor substrate-1 [IRS1; C/T versus C/C genotypes; OR, 4.3; 95% confidence interval (CI), 1.5-12.1] and three IL-6 receptor SNPs: rs6684439 (T/T versus C/C; OR, 2.9; 95% CI, 1.2-7.0), rs7529229 (C/C versus T/T; OR, 2.5; 95% CI, 1.1-6.0), and rs8192284 (C/C versus A/A; OR, 2.5, 95% CI, 1.1-6.0). Additional SNPs in genes encoding IGF-1, IGF binding protein-2, IRS2, and gp130 also showed suggestive associations with multiple myeloma risk. We conducted a large number of statistical tests, and the findings may be due to chance. Nonetheless, the data are consistent with the hypothesis that IGF-1-and IL-6-related gene variation influences susceptibility to multiple myeloma and warrant confirmation in larger populations.