Pharmacological evidence shows that cytochrome P450 2D6 (CYP2D6) function is important in the conversion of tamoxifen to its active metabolites. Many retrospective analyses have assessed the role of both CYP2D6 genotype and concurrent administration of drug inhibitors of CYP2D6 on outcome of tamoxifen therapy. These studies have frequently been of small size and their data highly variable. A published data meta-analysis of trials evaluating outcomes of tamoxifen therapy in early breast cancer was undertaken. Hazard ratios (HRs) were extracted for disease-free survival (DFS) and overall survival (OS). Pooled estimates were computed using inverse-variance and random-effect modeling. Data from 10 studies assessing CYP2D6 genotype were included in a meta-analysis. There was significant heterogeneity in the definition of comparison groups between studies. When compared to reduced CYP2D6 function, normal function was associated with a trend toward improved DFS (HR 2.07, 95% CI 0.96-4.49, P = 0.06) but not OS (HR 1.36, 95% CI 0.73-2.52, P = 0.34). Pooling of data from two studies evaluating CYP2D6 drug inhibitors showed that concomitant administration of these with tamoxifen was associated with a non-significant association with DFS (HR 1.37, 95% CI 0.69-2.73, P = 0.37). Analysis of the effect of CYP2D6 drug inhibitors on OS was not possible. The effect of CYP2D6 genotype on breast cancer seems to be relatively small and may not warrant testing of CYP2D6 genotype in all women with hormone receptor positive breast cancer. The effect of CYP2D6 genotype on outcome in low-risk patients may not be clinically relevant, while the upfront use of aromatase inhibitors is a reasonable alternative to tamoxifen in high-risk post-menopausal women, irrespective of CYP2D6 genotype. There are limited data supporting the association of potent inhibitors of CYP2D6 and detrimental outcome, but avoidance of such drugs seems reasonable.