ATP-binding cassette (ABC) transporters are major controllers of cholesterol efflux, though their role in membrane vesiculation, i.e. the release of microparticles, submicron fragments of plasma membranes, need to be defined. Here we investigated whether modifications of lipid transporters ABCA1 and ABCG1 could alter microparticle production, in basal and inflammatory conditions. We demonstrated that upregulation of ABC transporters with liver X receptor agonist T0901317 enhanced microparticle release by THP-1 cells. Conversely, the loss of ABCA1, but not ABCG1, blocked endotoxin/lipopolysaccharide (LPS)-induced microparticle production. Interestingly, the activation and phosphorylation of CREB by the PKA activator forskolin reduced the level of vesiculation whilst PKA inhibitor H89 enhanced it. Following the loss of ABCA1, there was no change to CREB phosphorylation. Furthermore, LPS-enhanced pCREB expression did not reduce, but rather induced, the production of microparticles. Together, our results indicate that ABCA1 is essential for agonist-enhanced vesiculation, which is suppressed by the phosphorylation of CREB protein. These findings indicate a novel mechanism by which targeting ABCA1 and pCREB may offer a therapeutic benefit for the inhibition of microparticle overproduction in sepsis and other inflammatory conditions.