With the application of genetic testing to contemporary medical diagnostics and practice, it has become apparent that the phenotypes of many disorders are modulated by host genetic factors. The aim of the current study was to determine whether selected single nucleotide polymorphisms (SNPs) unrelated to the human leukocyte antigen region or other immune pathways, including those associated with nonalcoholic fatty liver disease (NAFLD), may influence development, severity, or outcomes of drug-induced liver injury (DILI). Thirteen variants previously associated with NAFLD and/or selected other liver diseases were tested in 832 Caucasian DILI cases and 10,397 Caucasian population controls. DILI cases were attributed to multiple agents (177 individual drugs), with 56 cases due to herbal/dietary supplement products. Allele frequencies were imputed from recent genome-wide association studies and compared to those for European control samples from the Gnomad database. Significance was tested by linear regression or logistic regression, depending on the nature of the trait. Any variant that passed the Bonferroni threshold of P < 0.0004 ( ) was considered a significant association. None of the variants proved to be significantly associated with DILI as phenotype nor with any of the selected severity traits. Among the variants studied, rs1421085, found in the fat mass and obesity associated (FTO) gene, showed a marginal protective effect (odds ratio, 0.8; 95% confidence interval, 0.77-0.95; P = 0.005). None of the genetic polymorphisms tested were significantly associated with the risk of development, severity, or outcome of DILI. Conclusion: SNPs implicated in common liver diseases, such as NAFLD, do not play a substantial role in DILI pathogenesis across agents. It remains possible that these variants could be involved with DILI due to single agents, but this will require the evaluation of larger numbers of bona fide cases.