Increased mean platelet volume (MPV) is a marker of platelet activation. Platelet activation with cocaine use is not well studied. We wanted to investigate MPV levels in patients with cocaine-associated chest pain (CACP) as a marker of platelet activation. Retrospectively, MPV of 82 consecutive patients with CACP (group 1) with positive urine drug screen (UDS), without acute myocardial infarction (AMI) (group 1A) and with AMI with elevated troponin (group 1B), were included in the study. The control group (group 2) consisted of 89 consecutive patients admitted during the same time period with acute chest pain (ACP) who had negative UDS and negative cardiac markers with a normal cardiac stress test or normal coronary angiogram. Analysis showed no statistically significant difference of MPV between group 1, 8.46 ± 1.06 fL, versus group 2, 8.7 ± 1.07 fL; p = 0.142; and between group 1A, 8.46 ± 1.05 fL, and group 1B, 8.46 ± 1.09 fL; p = 0.983. By multiple linear regression analysis, MPV was not influenced by cocaine abuse (R = 0.269, R (2) = 0.072, adjusted R (2) = -0.009, p = 0.562). MPV is not elevated in patients with cocaine use even when they had AMI. Further studies may be necessary to investigate the role of platelet activation in patients with cocaine use and chest pain.