OBJECTIVES: To assess the associations of long-term lifestyle multidomain intervention (MI) and omega-3 supplementation with frailty level evolution and frailty incidence in community-dwelling older persons. DESIGN: Secondary analysis of the randomized controlled Multidomain Alzheimer Preventive Trial. SETTING: Thirteen memory centers in France and Monaco between 2008 and 2011. PARTICIPANTS: A total of 1588 community-dwelling persons aged 70 years or older with memory complaints (without dementia), slow gait speed, or limitation in one instrumental activity of daily living. INTERVENTION: A 3-year MI (43 group sessions including cognitive training, physical activity, and nutrition advice and three preventive consultations) plus daily omega-3 fatty acids, MI plus placebo, omega-3 alone, or placebo alone. MEASUREMENTS: The frailty phenotype (unintentional weight loss, exhaustion, low physical activity, slow gait, low handgrip strength: 0 to 5 score, higher is worse; a score of 3 or higher defines frailty) was assessed at baseline, 6, 12, 24, and 36 months. We used mixed-effect models for frailty level (0-5 score as an ordinal variable) and Cox models for frailty incidence. RESULTS: No differences were found between the intervention groups and placebo on the 3-year evolution of frailty level. Among 1394 non-frail participants at baseline, frailty incidence occurred in 134 (9.6%) persons: 26 (7.6%) in the MI plus omega-3 group, 34 (10%) in the omega-3 alone group, 31 (8.5%) in the MI plus placebo group, and 43 (12.3%) in the placebo-alone group). No differences regarding frailty incidence were found between intervention groups and placebo. After exclusion of 53 participants with incident frailty during the first year of follow-up, MI plus omega-3 was associated with a lower frailty incidence compared with placebo (hazard ratio = .43; 95% confidence interval = .22-.81). CONCLUSION: In community-dwelling older persons, the combination of a long-term lifestyle MI and omega-3 supplementation did not reduce frailty level or incidence. The reduction of frailty incidence associated with the combined intervention in a sensitivity analysis needs to be further confirmed. J Am Geriatr Soc 67:1700-1706, 2019.