We explored the interactive effects of endothelial nitric oxide synthase (eNOS) genotypes and cigarette smoking on protein levels and enzyme activity in 33 postpartum placentas. Whilst the eNOS protein levels were lower in the rare allele (0.48+/-0.11, n=9 vs. 1. 05+/-0.10, n=24, P<0.01), the eNOS enzyme activity was about 7-fold higher in the rare allele (4556.2+/-255.4 vs. 621.8+/-180.5 cpm/mg/min, P<0.01). Smokers had lower eNOS protein levels (1.07+/-0. 09 vs. 0.50+/-0.19, P<0.05) in both alleles. It reduced the eNOS activities only in the rare allele (non-smokers: 6143.8+/-251.2, n=5, smokers: 2968.5+/-259.4, n=4, 52% reduction, P<0.01). We conclude that associations between eNOS polymorphism and protein levels and enzyme activities are modifiable by smoking, the effects of smoking are dependent on the eNOS genotypes.