The aims of this study were to examine associations between two SNPs in the human IL-15 gene and three SNPs in the IL-15Ralpha gene with predictors of metabolic syndrome and phenotypes in muscle, strength, and bone at baseline and in response to resistance training (RT). Subjects were Caucasians who had not performed RT in the previous year and consisted of a strength cohort (n=748), volumetric cohort (n=722), and serum cohort (n=544). Subjects completed 12 weeks of unilateral RT of the non-dominant arm, using their dominant arm as an untrained control. ANCOVA analyses revealed gender-specific associations with: (1) IL-15 SNP (rs1589241) and cholesterol (p=0.04), LDL (p=0.02), the homeostasis model assessment (HOMA; p=0.03), and BMI (p=0.002); (2) IL-15 SNP (rs1057972) and the pre- to post-training absolute difference in 1RM strength (p=0.02), BMI (p=0.008), and fasting glucose (p=0.03); (3) IL-15Ralpha SNP (rs2296135) and baseline total bone volume (p=0.04) and the pre- to post-training absolute difference in isometric strength (p=0.01); and 4) IL-15Ralpha SNP (rs2228059) and serum triglycerides (p=0.04), baseline whole muscle volume (p=0.04), baseline cortical bone volume (p=0.04), and baseline muscle quality (p=0.04). All associations were consistent in showing a potential involvement of the IL-15 pathway with muscle and bone phenotypes and predictors of metabolic syndrome.