OBJECTIVE: To ascertain the relationship of physical inactivity and short-term all-cause mortality in a prospective cohort of randomly selected managed care organization members aged 40 years and older who have multiple chronic diseases. METHODS: Clinical databases were used to identify all health plan members aged 40 years and older with 2 or more chronic health conditions (hypertension, coronary heart disease, diabetes mellitus, or dyslipemia) in 1994. A random sample of 2336 members was surveyed by mail and telephone interview regarding their health-related behaviors. Survey data were linked to mortality data from the 1995 to 1997 Minnesota Death Index. Cox proportional hazards regression was used to ascertain the association between physical inactivity and subsequent all-cause mortality, adjusting for potential confounders. RESULTS: Members who reported less than 30 minutes a week of physical activity at baseline had a subsequent mortality risk ratio of 2.82 (P<.001) vs those with 30 or more minutes of physical activity a week. Increased mortality risk persisted (mortality risk ratio, 2.15; P<.001) after adjustments for age, sex, current smoking, functional impairment, and comorbidity score. CONCLUSIONS: In adults with chronic diseases, the physically inactive had higher observed mortality within a 42-month period. If physical inactivity reflects an independent mortality risk, efforts to maintain physical activity in such patients may yield significant clinical benefits within a short period. By contrast, if inactivity is primarily a proxy for other factors that elevate mortality risks, a simple physician inquiry regarding inactivity may help to identify patients at risk of death.