BACKGROUND: We tested the associations of a lifestyle multidomain intervention (MI), omega-3 supplementation (O3) or their combination with the change of clinically meaningful depressive symptoms in older adults. METHODS: Secondary analysis of the 3-year Multidomain Alzheimer Preventive Trial (MAPT), in which 1679 people, ≥70 years with memory complaints were randomized into: MI, O3, MI + O3, or placebo. MI was composed of nutritional and physical activity counselling and cognitive training. O3 supplementation corresponded to a daily dose of 1000 mg of omega-3. Discrete-time cox regressions were performed for each outcome. Three binary variables of incidence of depressive symptoms were created from the 15-item geriatric depression scale (GDS-15): minimum clinically meaningful depressive symptoms (≥2-point increase in GDS-15), moderate depressive symptoms (GDS-15 ≥ 5), and severe depressive symptoms (GDS-15 ≥ 10) DS. RESULTS: Discrete-time cox proportional hazards have found no associations for all of the analysis. The incidence of severe depressive symptoms across groups were, respectively: 1.1, 2.4, 2.3 and 2.5 per 100 person year for MI + O3, for O3, for MI, for placebo. There was a trend for a decreased risk of developing severe DS compared to placebo in the MI + O3 group (p = 0.085 after adjustment). CONCLUSIONS: To conclude, we did not find any association of a lifestyle multidomain intervention with the onset of clinically depressive symptoms in older adults with memory complaints. A study with a more intensive multidomain intervention might bring further insights on this topic.