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SummaryBackground: Cocaine produces adverse cardiovascular effects, some of which cannot be explained by epicardial coronary artery disease (CAD) or spasm.Hypothesis: The hypothesis of this study was that cocaine users would have increased coronary microvascular resistance, even in the absence of recent myocardial infarction (MI), CAD, or spasm.Methods: Microvascular resistance was assessed by the corrected Thrombolysis in Myocardial Infarction (TIMI) frame count (cTFC) method in a consecutive series of 59 cocaine users without acute or recent MI or angiographically significant epicardial stenosis (> 50%) or spasm. The cTFCs in these patients were compared with 21 normal controls and with published normal cTFC values.Results: The cTFC was significantly elevated (by 26-54%) in cocaine users. The cTFCs in the left anterior descending (LAD), circumflex (LCx), and right coronary (RCA) arteries in cocaine users were 30.0 ± 10.9, 34.1 ± 11.5, and 28.6 ± 11.8, respectively, compared with values in normal controls of 21.3 ± 4.3 (p = 0.001), 24.4 ± 7.2 (p = 0.001), and 22.7 ± 5.1 (p = 0.04), respectively, and published normal cTFC values (all p < 0.01). An abnormally high cTFC was present in 61% of patients in the LAD, 69% in the LCx, and 47% in the RCA.