Background: Data on the long-term benefits of nonspecific disease management programs are limited. We performed a long-term follow-up of a previously published randomized trial. Methods: We compared all-cause mortality and recurrent hospitalization during median follow-up of 7.5 years in a heterogeneous cohort of patients with chronic illness initially exposed to a multidisciplinary, home-based intervention (HBI) (n = 260) or to usual postdischarge care (n = 268). Results: During follow-up, HBI had no impact on all-cause mortality (relative risk, 1.04; 95% confidence interval, 0.80-1.35) or event-free survival from death or unplanned hospitalization (relative risk, 1.03; 95% confidence interval, 0.86-1.24). Initial analysis suggested that HBI had only a marginal impact in reducing unplanned hospitalization, with 677 readmissions vs 824 for the usual care group (mean ± SD rate, 0.72 ± 0.96 vs 0.84 ± 1.20 readmissions/patient per year; P = .08). When accounting for increased hospital activity in HBI patients with chronic obstructive pulmonary disease during follow-up for 2 years, post hoc analyses showed that HBI reduced readmissions by 14% within 2 years in patients without this condition (mean ± SD rate, 0.54 ± 0.72 vs 0.63 ± 0.88 readmission/patient per year; P = .04) and by 21% in all surviving patients within 3 to 8 years (mean ± SD rate, 0.64 ± 1.26 vs 0.81 ± 1.61 readmissions/patient per year; P = .03). Overall, recurrent hospital costs were significantly lower (14%) in the HBI group (mean ± SD, $823 ± $1642 vs $960 ± $1376 per patient per year; P = .045). Conclusion: This unique study suggests that a nonspecific HBI provides long-term cost benefits in a range of chronic illnesses, except for chronic obstructive pulmonary disease.