The objective of this study was to examine interindividual variability in codeine requirements and pain management by examining select genetic polymorphisms in the codeine pharmacological pathway. The study included a nested cohort of 98 women who were prescribed codeine following cesarean section. Participants were genotyped for select polymorphisms of the COMT, ABCB1, CYP2D6, UGT2B7 and OPRM1 genes and instructed to describe their level of pain using the visual analog scale (mm) 1 h following each dose of codeine. Analysis revealed that reported pain increases with maternal age (P=0.041). Asians required more codeine than Caucasians (P=0.048). Significant differences in mean dose consumption were seen among the genotypic groups of the OPRM1 A118G (P=0.001) and UGT2B7 C802T (P=0.015) variants. These variants were found to predict codeine consumption in the cohort overall (P=0.000) and among Caucasians (P=0.001). These findings will assist in customizing therapy to effectively manage postpartum pain.The Pharmacogenomics Journal advance online publication, 10 March 2015; doi:10.1038/tpj.2015.3.