HIV-positive patients are at increased risk for coronary artery disease (CAD); changes in platelet activation may play a role. This study was performed to determine if levels of soluble glycoprotein VI (sGPVI), a platelet-specific marker of activation, were different in HIV-positive patients compared with HIV-negative controls and further if levels were predictive of CAD in HIV. Twenty-four HIV-positive individuals (HIV cases) with CAD were compared with 46 age- and sex-matched HIV-positive controls without CAD and 41 HIV-negative controls (healthy controls). Platelet activation (represented by sGPVI level) was compared 12 months and 1 month prior to CAD diagnosis. sGPVI was quantified by ELISA. sGPVI levels were higher in HIV-positive subjects (combined) than healthy controls (122.5 ng/mL [interquartile ranges (IQR) 90.3-160.5] versus 84.7 ng/mL [IQR 48.6-119.5], p <0.001). Twelve months before the event, there was no difference in sGPVI between HIV cases and HIV controls (113.4 ng/mL [IQR 85.6-141.65] versus 128.0 ng/mL [IQR 96.6-179.4], p = 0.369). One month prior to the event, sGPVI was significantly lower in HIV cases compared with HIV controls (109.0 ng/mL [IQR 79.4-123.4] versus 133.9 ng/mL [IQR 112.7-171.9], p = 0.010). These results remained significant following adjustment for possible confounders. This work demonstrates that HIV infection is associated with higher sGPVI levels. A fall in sGPVI immediately prior to first coronary artery event may reflect a loss of negative-feedback mechanism and be an important pathological step in the development of symptomatic CAD, but further work is needed to confirm these findings and determine their clinical impact.