Purpose Handgrip strength is a simple measurement used to estimate overall muscle strength but might also serve as a predictor of health-related prognosis. We investigated grip strength-mortality association in a longitudinal study. Methods A total of 4912 persons (1695 men and 3217 women), 35 to 74 years old at baseline, were the subjects of this study. Members of the Adult Health Study (AHS) cohort in Hiroshima, Japan, these individuals underwent a battery of physiological tests, including handgrip-strength testing, between July 1970 and June 1972. Mortality was followed until the end of 1999. Estimates of relative risk (RR) of mortality associated with grip strength were adjusted for potentially confounding factors by Cox proportional hazard analysis. Results Multivariate-adjusted RR of all causes of death, except for external causes, for the highest quintile of grip strength in men was 0.52 (95% confidence interval [CI], 0.33-0.80) for the age group 35-54 years, 0.72 (95% CI, 0.53-0.98) for the ages 55-64 years, and 0.67 (95% CI, 0.49-0.91) for the ages 65-74 years. These figures were significantly lower than the RR for the reference group (the third quintile). Similar trends were observed in women. Multivariate-adjusted RR of all causes of death except external causes for each 5-kg increment of grip strength was significantly low (RR: 0.89, 95% CI, 0.86-0.92 for men, RR: 0.87, 95% CI, 0.83-0.92 for women). Multivariate-adjusted RR for heart disease, stroke, and pneumonia in men was 0.85 (95% CI, 0.79-0.93), 0.90 (95% CI, 0.83-0.99), and 0.85 (95% CI, 0.75-0.98), respectively. RR for each 5-kg increment of grip strength remained 0.92 (95% CI, 0.87-0.96), even after more than 20 years of follow-up. Conclusion Grip strength is an accurate and consistent predictor of all causes of mortality in middle-aged and elderly persons.