OBJECTIVES: To evaluate the association between six nondisease-specific problems (problems that cross multiple domains of health) and mortality in middle-aged and older adults. DESIGN: Prospective, observational cohort. SETTING: U.S. population sample. PARTICIPANTS: Participants included 23,669 black and white U.S. adults aged 45 and older enrolled in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study. MEASUREMENTS: Nondisease-specific problems included cognitive impairment, depressive symptoms, exhaustion, falls, impaired mobility, and polypharmacy. Age-stratified (<65, 65-74, ≥ 75) hazard ratios for all-cause mortality were calculated for each problem individually and according to number of problems. RESULTS: One or more nondisease-specific problems occurred in 40% of participants younger than 65, 45% of those aged 65 to 74, and 55% of those aged 75 and older. Compared with participants with none of these problems, the multivariable adjusted hazard ratio for all-cause mortality associated with each additional nondisease-specific problem was 1.34 (95% confidence interval (CI) = 1.23-1.46) for participants younger than 65, 1.24 (95% CI = 1.15-1.35) for those aged 65 to 74, and 1.30 (95% CI = 1.21-1.39) for those aged 75 and older. CONCLUSION: Nondisease-specific problems were associated with mortality across a wide age spectrum. Future studies should explore whether treating these problems will improve survival and identify innovative healthcare models to address multiple nondisease-specific problems simultaneously.