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Context: Obesity in midlife is a risk factor for dementia, but it is unknown if caloric restriction-induced weight loss could prevent cognitive decline and therefore dementia in elderly patients with cognitive impairment., Objective: To evaluate the cognitive effect of intentional weight loss in obese elderly patients with mild cognitive impairment (MCI), considering the influence of age, apolipoprotein E (APOE) genotype, physical activity, biochemical markers, and diet., Design: Single-center, prospective controlled trial., Setting: Academic medical center., Participants: Eighty obese patients with MCI, aged 60 or older (68.1 ± 4.9 y, body mass index [BMI] 35.5 ± 4.4 kg/m(2), 83.7% women, 26.3% APOE allele ϵ4 carriers)., Intervention: Random allocation to conventional medical care alone (n = 40) or together with nutritional counselling (n = 40) in group meetings aiming to promote weight loss through caloric restriction for 12 months., Outcome Measurements: clinical data, body composition, neuropsychological tests (main outcome), serum biomarkers, APOE genotype, physical performance, dietary recalls., Results: Seventy-five patients completed the follow-up. BMI, on average, decreased 1.7 ± 1.8 kg/m(2) (P = .021), and most of the cognitive tests improved, without difference between the groups. In analysis with linear generalized models, the BMI decrease was associated with improvements in verbal memory, verbal fluency, executive function, and global cognition, after adjustment for education, gender, physical activity, and baseline tests. This association was strongest in younger seniors (for memory and fluency) and in APOE allele ϵ4 carriers (for executive function). Changes in homeostasis model assessment-estimated insulin resistance, C-reactive protein, leptin and intake of energy, carbohydrates, and fats were associated with improvement in cognitive tests., Conclusions: Intentional weight loss through diet was associated with cognitive improvement in patients with MCI.