It is the second decade of controversy regarding the cardiovascular effects of cyclo-oxygenase-2 (COX-2) inhibitors. At this time, celecoxib is the only available COX-2-specific inhibitor for treatment of pain and inflammation. Therefore, the present study was designed primarily to determine the impact of celecoxib on cholesterol handling (uptake via scavenger receptors and efflux from the cells) and foam cell formation in human THP-1 macrophages, followed by comparison to rofecoxib and other non-steroidal anti-inflammatory drugs (NSAIDs). THP-1 human macrophages and peripheral blood mononuclear cells were incubated with: celecoxib, rofecoxib, naproxen (at 5, 10, 25 µM) and acetaminophen (0.5 mM, 1 mM)±oxidized low-density lipoprotein (oxLDL, 25 µg/mL). Scavenger receptors: CD36, LOX-1, SR-A1, and CXCL16 and cholesterol efflux proteins: ATP-binding cassette transporter (ABC) A1 and G1, and 27-hydroxylase were detected. The adhesion of monocytes to cultured endothelial cells with/ without COX-2 inhibitors/NSAIDs was also analyzed. The presence of celecoxib and rofecoxib (at high concentrations) significantly decreased expression of 27-hydroxylase and ABCA1, interfering with normal cholesterol outflow from macrophages. Acetaminophen and the non-specific COX inhibitor naproxen had no significant effect on these proteins. Only celecoxib had a profound effect on the class B scavenger receptor CD36 and the class E receptor LOX1. We demonstrate that in contrast to celecoxib, rofecoxib and naproxen increased adhesive properties of monocytes to endothelial cells. This work might contribute to our understanding of multiple mechanisms underlying elevated cardiovascular risk upon the use of COX-2 inhibitors and uncover new possibilities to enhance the safety profile of existing COX-2 inhibitors.