Imatinib has a mild toxicity profile, although severe adverse events may develop. In this pharmacogenetic pathway analysis the need for dose reduction and cessation of therapy was tested for an association with single nucleotide polymorphisms (SNPs) in genes related to imatinib pharmacology. Retrospective data from 315 patients with a gastrointestinal stromal tumor who received imatinib 400 mg o.d. was associated with 36 SNPs. SNPs that showed a trend in univariate testing were tested in a multivariate model with clinical factors and correction for multiple testing was performed. Dose reduction was associated with carriership of the A-allele in rs2231137 in ABCG2 (OR 7.35, p = 0.0002) and two C-alleles in rs762551 in CYP1A2 (OR 7.12, p = 0.001). Results remained significant after correction for multiple testing. Therapy cessation did not show an association with any of the tested SNPs. These results may help identifying patients at increased risk for toxicity who could benefit from intensified follow-up.