ScopeMacrophage plasticity allows adapting to different environments, having a dual activity in inflammatory‐related diseases. Our hypothesis is that the type of dietary fatty acids into human postprandial triglyceride‐rich lipoproteins (TRLs), alone or in combination with niacin (vitamin B3), could modulate the plasticity of monocytes‐macrophages.Methods and resultsWe isolated TRLs at the postprandial peak from blood samples of healthy volunteers after the ingestion of a meal rich in saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs) or MUFAs plus omega‐3 long‐chain polyunsaturated fatty acids (LCPUFAs). Autologous monocytes isolated at fasting were first induced to differentiate into naïve macrophages. We observed that postprandial TRL‐MUFAs, particularly in combination with niacin, enhance competence to monocytes to differentiate and polarise into M2 macrophages. Postprandial TRL‐SFAs made polarised macrophages prone to an M1 phenotype. In contrast to dietary SFAs, dietary MUFAs in the meals plus immediate‐release niacin primed circulating monocytes for a reduced postprandial pro‐inflammatory profile.ConclusionOur study underlines a role of postprandial TRLs as a metabolic entity in regulating the plasticity of the monocyte‐macrophage lineage and also brings an understanding of the mechanisms by which dietary fatty acids are environmental factors fostering the innate immune responsiveness in humans.