Pharmacogenetics studies have identified several allelic variants with the potential to reduce toxicity and improve treatment outcome. The present study was designed to determine if such findings are reproducible in a heterogenous population of patients with lung cancer undergoing therapy with paclitaxel. We designed a prospective multi-institutional study that recruited n = 103 patients receiving paclitaxel therapy with a 5-year follow up. All patients were genotyped using the Drug Metabolizing Enzymes and Transporters (DMET) platform, which ascertains 1931 genotypes in 235 genes. Progression-free survival (PFS) of paclitaxel therapy and clinically-significant paclitaxel toxicities were classified and compared according to genotype. Initial screening revealed eleven variants that are associated with PFS. Of these, seven variants in ABCB11 (rs4148768), ABCC3 (rs1051640), ABCG1 (rs1541290), CYP8B1 (rs735320), NR3C1 (rs6169), FMO6P (rs7889839), and GSTM3 (rs7483) were associated with paclitaxel PFS in a multivariate analysis accounting for clinical covariates. Multivariate analysis revealed four SNPs in VKORC1 (rs2884737), SLC22A14 (rs4679028), GSTA2 (rs6577), and DCK (rs4643786) were associated with paclitaxel toxicities. With the exception of a variant in VKORC1, the present study did not find the same genetic outcome associations of other published research on pharmacogenetics variants that affect paclitaxel outcomes. This finding suggests that prior pharmacogenomics research findings may not be reproduced in the most frequently-diagnosed malignancy, lung cancer.