This work examines whether the increased all-cause and cardiovascular disease (CVD) mortality associated with polypharmacy could be offset by a healthy lifestyle. We included a prospective cohort of 3,925 individuals representative of the Spanish population aged ≥60 years, who were recruited in 2000-2001 and followed up through 2014. Polypharmacy was defined as treatment with ≥5 medications. The following lifestyle behaviors were considered healthy: not smoking, eating a healthy diet, being physically active, moderate alcohol consumption, low sitting time, and adequate sleep duration. Individuals were classified into three lifestyle categories s: unfavorable (0-2), intermediate (3-4) favorable (5-6). Over a median 13.8-y follow-up, 1,822 all-cause and 675 CVD deaths occurred. Among individuals with polypharmacy, intermediate and favorable lifestyles were associated with an all-cause mortality reduction (95% confidence interval [CI]) of 47% (34-58%) and 54% (37-66%), respectively; 37% (9-56%) and 60% (33-76%) for CVD death, respectively. The theoretical adjusted hazard ratio (95%CI) associated with replacing 1 medication with 1 healthy lifestyle behavior was 0.73 (0.66-0.81) for all-cause death and 0.69 (0.59-0.82) for CVD death. The theoretical adjusted hazard ratio (95%CI) for all-cause and CVD mortality associated with simply reducing 1 medication was 0.88 (0.83-0.94) and 0.83 (0.76-0.91), respectively. Hence, adherence to a healthy lifestyle behavior can reduce mortality risk associated with polypharmacy in older adults.