Apoptosis is a distinct mode of cell death that is responsible for the deletion of cells in tumors and in normal tissues. We pursued a pathway-based approach to investigate the association of potentially functional genetic polymorphisms of the corresponding genes with the outcomes of platinum-based chemotherapy in advanced non-small-cell lung cancer (NSCLC). A MALDI-TOF mass spectrometer was used for genotyping 10 polymorphisms of eight apoptosis-related genes, including BCL2 rs1801018, rs1564483, rs2279115, BAX rs4645878, caspase (CASP3) rs6948, CASP8 rs3834129, CASP10 rs13006529, rs3900115, tumor necrosis factor α (TNFα) rs1800629, and macrophage migration inhibitory factor (MIF) rs755622. The associations between these single nucleotide polymorphisms and the outcomes of 445 advanced NSCLC patients treated with platinum-based chemotherapy were evaluated. The CASP3 rs6948 polymorphism was most significantly associated with hematologic toxicity in a dose-dependent manner. The incidence of severe hematologic toxicity was significantly lower in C allele carriers (= 0.005; odds ratio = 0.524; 95% confidence interval = 0.333–0.824) and still significant after a Bonferroni correction. The function of this single nucleotide polymorphism in gene expression was also investigated. Quantitative PCR showed that individuals with the C allele had lower levels of CASP3 transcripts in peripheral blood lymphocytes. Luciferase reporter assays showed that the minor C allele significantly decreased the reporter gene expression level. In addition, the TNFα rs1800629 mutant allele significantly elevated gastrointestinal toxicity (= 0.020; odds ratio = 3.020; 95% confidence interval = 1.188–7.676), when compared to the wild-type homozygote. No other association was found. In conclusion, for the first time, our study suggests that CASP3 rs6948 might influence CASP3 expression and be associated with severe hematologic toxicity risk. (Cancer Sci, doi: 10.1111/j.1349-7006.2012.02323.x, 2012)