Long-term safety of consuming low-carbohydrate diets (LCD) in Asian populations, whose carbohydrate intake is relatively high, is not known. In the present study, the association of LCD with CVD and total mortality was assessed using data obtained in the NIPPON DATA80 (National Integrated Project for Prospective Observation of Non-communicable Disease and Its Trends in the Aged 1980) during 29 years of follow-up. At baseline in 1980, data were collected from study participants aged ≥ 30 years from randomly selected areas in Japan. LCD scores were calculated based on the percentage of energy as carbohydrate, fat and protein, estimated by 3 d weighed food records. A total of 9200 participants (56% women, mean age 51 years) were followed up. During the follow-up, 1171 CVD deaths (52% in women) and 3443 total deaths (48% in women) occurred. The multivariable-adjusted hazard ratio (HR) for CVD mortality using the Cox model comparing the highest v. lowest deciles of LCD score was 0·60 (95% CI 0·38, 0·94; P(trend) = 0·021) for women and 0·78 (95% CI 0·58, 1·05; P(trend) = 0·079) for women and men combined; the HR for total mortality was 0·74 (95% CI 0·57, 0·95; P(trend) = 0·029) for women and 0·87 (95% CI 0·74, 1·02; P(trend) = 0·090) for women and men combined. None of the associations was statistically significant in men. No differential effects of animal-based and plant-fish-based LCD were observed. In conclusions, moderate diets lower in carbohydrate and higher in protein and fat are significantly inversely associated with CVD and total mortality in women.