Without data from randomized trials, the long-term effects of fish consumption on coronary heart disease (CHD) need to be inferred from observational studies. We estimated CHD risk under different hypothetical interventions on fish consumption during mid- and later life in 2 prospective US cohorts of 25,797 men in the Health Professionals Follow-Up Study and 53,772 women in the Nurses’ Health Study. Participants provided information on risk factors and disease every 2 years and on diet every 4 years. We adjusted for baseline and time-varying risk factors for CHD by using the parametric g-formula (where g stands for “generalized”). We observed 1,865 incident CHD cases among men (in 1990–2008) and 1,891 CHD cases among women (in 1986–2008). The risk ratios for CHD when comparing the risk if everyone had consumed at least 2 servings of fish per week with the risk if no one consumed fish during the follow-up periods were 1.03 (95% confidence interval: 0.90, 1.15) for men and 0.87 (95% confidence interval: 0.76, 0.98) for women. Our results suggest that increasing fish consumption to at least 2 servings per week in mid- or later life may lower CHD risk in women but not in men. Our analytical approach allowed us to explicitly specify hypothetical interventions and to assess the effectiveness of dietary changes in midlife.