Background: Cisplatin is widely used and highly ototoxic; we sought to identify genetic variants that modulate cisplatin-related hearing loss. Methods: We performed a GWAS for cisplatin-related hearing loss in 512 patients of European genetic ancestry enrolled in an ongoing multi-center North American clinical study of TCS. The geometric mean of air conduction thresholds measured at 4, 6, 8, 10 and 12 kHz was the quantitative phenotype used in the GWAS. SNPs were genotyped on the Illumina HumanOmniExpressExome chip and imputed using the 1000 Genomes reference panel, with 5.1 million SNPs passing quality control for GWAS inclusion. Covariates included in the GWAS were age at audiometry, cumulative cisplatin dose, and 10 genotypic principal components. Results: One SNP, rs62283056, in the first intron of WFS1 met genome-wide significance for association with cisplatin-associated hearing loss (P = 4.8 x 10^-9). Mutations in this gene can cause autosomal dominant deafness and Wolfram syndrome, also called DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness). The minor allele of rs62283056 (frequency 0.21 in the GWAS cohort) associates with increased hearing loss and decreased expression of WFS1 (cis-eQTL) in several human tissues from the GTEx Project, including cerebellar hemisphere, tibial nerve and thyroid. WFS1 is differentially expressed in the human inner ear (cochlea vs. vestibule, P_adj = 0.032, Schrauwen et al. Hear Res 2015). We found a significant interaction between rs62283056 genotype and cumulative cisplatin dose (P = 0.029), indicating higher dose may exacerbate the hearing loss effect in patients carrying the minor allele. When hearing loss is dichotomized as a geometric mean > 20 dB (n = 242 affected), the allelic OR for hearing loss risk is 1.9 [95% CI: 1.3 – 2.8]. Conclusions: The WFS1 SNP is the first report of a genome-wide significant association with cisplatin-related hearing loss in adults. Expression data and known gene function corroborate its potential involvement in hearing loss. Future studies will focus on replicating and extending the genetic and mechanistic findings discovered here.