We sought to determine prospective changes in health-related quality of life (HRQoL) measures and subsequent mortality in middle-aged and older women. We obtained data from 40 337 healthy women from the Nurses' Health Study aged 46 to 71 years in 1992. We used Cox proportional hazards regression to evaluate associations of changes in self-assessed physical and mental component summary (PCS and MCS) scores from the Short Form 36 Health Survey between 1992 and 1996 and between 1996 and 2000, with all-cause mortality through 2004. Women with low HRQoL (PCS and MCS scores) and the greatest HRQoL declines had higher mortality than did women with stable scores. Change in PCS score predicted mortality across the range of 4-year change: severe decline (relative risk [RR] = 3.32; 95% confidence interval [CI] = 2.45, 4.50), moderate decline (RR = 1.44; 95% CI = 1.16, 1.79), slight decline (RR = 1.35; 95% CI = 1.12, 1.63), no change (reference category), improvement (RR = 0.72; 95% CI = 0.56, 0.91; continuous P < .001). MCS score results were similar. Score increases were associated with lifestyle improvements, especially increased physical activity. Observed associations demonstrate the predictive validity of changes in self-assessed HRQoL for subsequent mortality in healthy populations. Future research should examine determinants of patterns of change.