Oxaliplatin is frequently used as part of a chemotherapeutic regimen with 5‐fluorouracil in the treatment of colorectal cancer (CRC). The cellular availability of oxaliplatin is dependent on metabolic and transporter enzymes. Variants in genes encoding these enzymes may cause variation in response to oxaliplatin and could be potential predictive markers. Therefore, we used a two‐step procedure to comprehensively investigate 1,444 single nucleotide polymorphisms (SNPs) from these pathways for their potential as predictive markers for oxaliplatin treatment, using 623 stage II–IV CRC patients (of whom 201 patients received oxaliplatin) from a German prospective patient cohort treated with adjuvant or palliative chemotherapy. First, all genes were screened using the global test that evaluated SNP*oxaliplatin interaction terms per gene. Second, one model was created by backward elimination on all SNP*oxaliplatin interactions of the selected genes. The statistical procedure was evaluated using bootstrap analyses. Nine genes differentially associated with overall survival according to oxaliplatin treatment (unadjusted p values < 0.05) were selected. Model selection resulted in the inclusion of 14 SNPs from eight genes (six transporter genes, ABCA9, ABCB11, ABCC10, ATP1A1, ATP1B2, ATP8B3, and two metabolism genes GSTM5, GRHPR), which significantly improved model fit. Using bootstrap analysis we show an improvement of the prediction error of 3.7% in patients treated with oxaliplatin. Several variants in genes involved in metabolism and transport could thus be potential predictive markers for oxaliplatin treatment in CRC patients. If confirmed, inclusion of these variants in a predictive test could identify patients who are more likely to benefit from treatment with oxaliplatin. What's new? Oxaliplatin frequently is used in combination with 5‐fluorouracil and leucovorin as a first‐line therapy against colorectal cancer (CRC). However, the efficacy of oxaliplatin differs greatly between patients. Oxaliplatin availability to cells and its subsequent detoxification depend on the activity of certain metabolic and transporter enzymes, some of which, according to this study, carry genetic variants that alter the drug's effectiveness. The authors show that interactions between oxaliplatin and single nucleotide polymorphisms (SNPs) in multiple transporter and metabolism genes are associated with overall CRC survival. The SNPs could be used to predict the likelihood of response to oxaliplatin.