Although most patients with small-cell lung cancer respond to chemotherapy, the survival time is highly diverse. We conducted a genome-wide analysis to examine whether germline genetic variations are prognostic factors in small-cell lung cancer patients treated with the same chemotherapy regimen. Genome-wide scan of single nucleotide polymorphisms (SNP) was performed using blood DNA to identify genotypes associated with overall survival in 245 patients treated with platinum-based chemotherapy, and the results were replicated in another independent set of 305 patients. Associations were estimated by Cox models and function of the variants was examined by biochemical assays. We found that rs1820453 T>G SNP within the promoter region of YAP1 on chromosome 11q22 and rs716274 A>G SNP in the region of downstream of DYNC2H1 on chromosome 11q22.3 are associated with small-cell lung cancer survival. In pooled analysis of 2 independent cohorts, the adjusted hazard ratio for patients with the rs1820453 TG or GG genotype was 1.49 (95% CI, 1.19-1.85; P = 0.0004) and 1.65 (95% CI, 1.36-2.01; P = 4.76 × 10(-7)), respectively, compared with the TT genotype; and for patients with the rs716274 AG or GG genotype was 1.83 (95% CI, 1.47-2.29; P = 8.74 × 10(-8)) and 2.96 (95% CI, 1.90-4.62; P = 1.59 × 10(-6)), respectively, compared with the AA genotype. Functional analysis showed that the rs1820453 T>G change creates a transcriptional factor binding site and results in downregulation of YAP1 expression. These results suggest that YAP1 may play an important role in prognosis of small-cell lung cancer patients treated with platinum-based chemotherapy.