Genetic variation may be an important risk factor for multiple myeloma. A hallmark of tumor formation and growth is cell cycle dysregulation and apoptosis avoidance. We previously reported the association of genetic variation in caspase genes, the apoptotic-regulating family, and multiple myeloma risk. To further examine if genetic variation in key cell cycle and apoptosis genes alters multiple myeloma risk, we genotyped 276 tag SNPs in 27 gene regions in a population-based case-control study of non-Hispanic Caucasian women (108 cases; 482 controls) in Connecticut. Logistic regression assessed the effect of each SNP on multiple myeloma risk and the minP test assessed the association at the gene region level. Three gene regions were significantly associated with risk of multiple myeloma (BAX minP=0.018, CASP9 minP=0.025, and RIPK1 minP=0.037). Further explorations identified the most significant variant of BAX, RIPK1, and CASP9 to be rs1042265, rs9391981, and rs751643, respectively. The A variant at rs1042265 (OR(GA+AA)=0.40, 95% CI=0.21-0.78) and the C variant at rs9391981 (OR(GC+CC)=0.32, 95% CI=0.12-0.81) were associated with a decreased risk of multiple myeloma. The G variant at rs7516435 was associated with an increased risk of multiple myeloma (OR(AG)=1.48, 95% CI=0.94-2.32; OR(GG)=2.59, 95% CI=1.30-5.15; p(trend)=0.005). Haplotype analyses supported the SNP findings. These findings suggest that genetic variation in cell cycle and apoptosis genes may play a key role in multiple myeloma and warrant further investigation through replication studies.