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Cyclophosphamide is a commonly used cancer agent that is metabolically activated by polymorphic enzymes. This study aims to investigate the association between predicted activity of candidate pharmacogenes with severe toxicity during cyclophosphamide treatment.Genome-wide genetic data was collected from an institutional genetic data repository for CYP2B6, CYP3A4, CYP2C9, CYP2C19, GSTA1, GSTP1, ALDH1A1, ALDH3A1, ABCC1, ABCB1, and ERCC1. Treatment and toxicity data were retrospectively collected from the patient's medical record. The a priori selected primary hypothesis was that patients who have CYP2B6 reduced metabolizer activity (poor or intermediate (PM/IM) vs. normal (NM) metabolizer) have lower risk of severe toxicity or cyclophosphamide treatment modification due to toxicity.In the primary analysis of 510 cyclophosphamide-treated patients with available genetic data, there was no difference in the odds of severe toxicity or treatment modification due to toxicity in CYP2B6 PM/IM vs. NM (odds ratio = 0.97, 95% Confidence Interval: 0.62-1.50, p = 0.88). In an exploratory, statistically uncorrected secondary analysis, carriers of the ALDH1A1 rs8187996 variant had a lower risk of the primary toxicity endpoint compared with wild-type homozygous patients (odds ratio = 0.31, 95% Confidence Interval: 0.09-0.78, p = 0.028). None of the other tested phenotypes or genotypes was associated with the primary or secondary endpoints in unadjusted analysis (all p 0.05).The finding that patients who carry ALDH1A1 rs8187996 may have a lower risk of cyclophosphamide toxicity than wild-type patients contradicts a prior finding for this variant and should be viewed with skepticism. We found weak evidence that any of these candidate pharmacogenetic predictors of cyclophosphamide toxicity may be useful to personalize cyclophosphamide dosing to optimize therapeutic outcomes in patients with cancer.