The uptake of oxidized LDL (oxLDL) by macrophages leads to foam cell formation and fatty streaks, which represent early sites of potential atheroma development. We have developed a cell culture model of chronic oxLDL-exposure to determine if hallmark parameters of oxLDL-uptake and cytotoxicity are altered during foam cell formation and to determine changes in protein and mRNA expression that distinguish acute and chronic oxLDL-exposure. Though the extent of oxLDL-uptake did not change, a resistance to oxLDL-induced cytotoxicity was observed in the chronically-exposed cells. Macrophages that have been chronically-exposed to oxLDL required a 40% higher concentration of oxLDL to achieve 50% survival in a 48-hour treatment, relative to macrophages subjected to a single oxLDL exposure. A main feature of the differentially expressed proteome was a series of significantly overexpressed antioxidant and antioxidant-related proteins in the oxLDL-exposed cells. A large proportion of these proteins (45%) were overexpressed in the chronically exposed cells prior to the oxLDL treatment, indicative of the unique phenotype produced by the chronic treatment. Analysis of the transcriptome also revealed a broad increase in the expression of antioxidant and antioxidant-related proteins. In addition, the transcriptome experiments found an increased inflammatory response under conditions of both acute and chronic oxLDL-exposure. Overall, the combined functional, proteomic, and transcriptomic experiments show that macrophages respond to oxLDL by developing an oxidative stress-resistance that increases and stabilizes with chronic exposure. Further, this protective response and the increased foam cell survival that it supports amplifies their pro-atherogenic role by promoting a continued inflammatory state.