Seafood/fish intake has been regarded as a protective factor for coronary heart disease (CHD), while smoking is a strong risk factor. To examine whether associations between smoking and risk of CHD are modified by seafood/fish intake, we studied 72,012 Japanese men and women aged 45-74 years who completed 2 food frequency questionnaires, 5 years apart, during the period 1995-2009. After 878,163 person-years of follow-up, 584 incident cases of CHD (101 fatal and 483 nonfatal), including 516 myocardial infarctions, were documented. There was a clear dose-response association between smoking and CHD risk among subjects with a low seafood/fish intake (<86 g/day) but not among those with a high seafood/fish intake (≥86 g/day). Compared with never smokers, the multivariable hazard ratios in light (1-19 cigarettes/day), moderate (20-29 cigarettes/day), and heavy (≥30 cigarettes/day) smokers were 2.39 (95% confidence interval (CI): 1.60, 3.56), 2.74 (95% CI: 1.90, 3.95), and 3.24 (95% CI: 2.12, 4.95), respectively, among low seafood/fish eaters and 1.13 (95% CI: 0.64, 1.99), 1.29 (95% CI: 0.95, 2.04), and 2.00 (95% CI: 1.18, 3.51), respectively, among high seafood/fish eaters. Compared with heavy smokers with a low seafood/fish intake, light smokers with a high seafood/fish intake had substantially reduced risk of CHD (hazard ratio = 0.57, 95% CI: 0.32, 0.98). High seafood/fish intake attenuated the positive association between smoking and risk of CHD.