The innate immune system of patients with Alzheimer’s disease and mild cognitive impairment (MCI) is deregulated with highly increased or decreased transcription of inflammatory genes and consistently depressed phagocytosis of amyloid-b1-42 (Ab) by monocytes and macrophages. Current immune therapies target single mechanisms in the adaptive immune system but not innate immunity. Here, we summarize recent advances in therapy by v-3, v-6, and epoxy fatty acids; specialized proresolving mediators; and vitamin D3 that have proven immune effects and emerging cognitive effects in patients with MCI. The hypothesis of this approach is that macrophages of normal participants, but not those of patients with Alzheimer’s disease and MCI, possess effective phagocytosis for Ab and protect homeostasis of the brain and, furthermore, that defective MCI macrophages recover phagocytic function via v-3. Recent studies of fish-derived v-3 supplementation in patients with MCI have shown polarization of Apo«3/«3 patients’ macrophages to an intermediate M1-M2 phenotype that is optimal for Ab phagocytosis and the stabilization of cognitive decline. Therefore, accumulating preclinical and preliminary clinical evidence indicates that v-3 supplementation should be tested in a randomized controlled clinical trial and that the analysis should involve the apolipoprotein E genotype and intervening conditions during trial.—Fiala, M., Kooij, G., Wagner, K., Hammock, B., Pellegrini, M. Modulation of innate immunity of patients with Alzheimer’s disease by omega-3 fatty acids.