Clinical studies of drug-eluting stents delivering the mammalian target of rapamycin (mTOR) inhibitor, rapamycin (Sirolimus), have demonstrated a reduced efficacy for these devices in patients with diabetes, which suggests that the mTOR pathway may cease to be dominant in mediating the vascular response to injury under diabetic conditions. We hypothesized that changes in serum composition accompanying diabetes may reduce the role of mTOR in mediating the vascular response to injury. We measured the ability of a median dose of rapamycin (10 nM) to inhibit the proliferation of human coronary artery smooth muscle cells (huCASMCs) stimulated with serum obtained from donors with diabetes (n = 14) and without diabetes (n = 16). In an additional analysis, we compared the effects of rapamycin on huCASMCs stimulated with the serum of donors with metabolic syndrome (n = 15) versus those without (n = 7). There was no difference in the effect of rapamycin on huCASMC proliferation after stimulation with serum from either donors with diabetes or donors with metabolic syndrome compared with the respective controls. We conclude that the changes in the serum composition common to diabetes and metabolic syndrome are insufficient to diminish the role of mTOR in the progression of cardiovascular disease.