Hypercholesterolemia is a major risk factor for macrophage dysfunction, including release of multiple proinflammatory cytokines. In this study, we address a hypothesis that membrane potential is one of the mechanisms contributing to lipoprotein‐induced macrophage dysfunction. Our earlier studies showed that an increase in cellular cholesterol suppresses inwardly‐rectifying K+ channels (Kir) in endothelial cells in vitro and in vivo. Here we show that Kir current is also suppressed by cholesterol in alveolar and in bone marrow‐derived macrophages. Specifically, we show that macrophage Kir are suppressed by enriching the cells with cholesterol using methyl‐b‐cyclodextrin or by exposing them to acetylated LDL. In cotrast, HDL results in a decrease in the level of cellular cholesterol and induces an increase in Kir. Furthermore, unexpectedly, exposing macrophages to oxLDL also significantly increases the amplitude of the current. In this case, however, the level of membrane cholesterol is not affected. We suggest, therefore, that the similarities between the effects of cholesterol depletion, HDL and oxLDL may be due to their effects on lipid packing. Finally, we show that blocking Kir currents results in a significant increase in the production of interleukins 1α and β suggesting that membrane depolarization contributes to the inflammatory response of the macrophages under high cholesterol conditions.