Background: HIV patients on protease inhibitors have greater risk of acute coronary syndromes (ACS) but little is known about treatment-naïve patients. Methods and Results: Authors conducted a prospective single-center study from Soweto, South Africa, comparing the clinical and angiographic features of treatment-naïve HIV positive and negative patients with ACS. Between March 2004 and February 2008, 30 consecutive treatment-naïve HIV patients with ACS were compared to the next HIV-negative patient as a 1:1 control. HIV patients were younger (43 ± 7 vs. 54 ± 13, P = 0.004) and, besides smoking (73% vs. 33%, P = 0.002), had fewer risk factors than the control group with less hypertension (23% vs. 77%, P = 0.0001), diabetes (3% vs. 23%, P = 0.05), LDL hyperlipidemia (2.2 ± 0.9 vs. 3.0 ± 1.2, P = 0.006), and other coronary risk factors (7% vs. 53%, P = 0.0001). HDL was lower in the HIV group (0.8 ± 0.3 vs. 1.1 ± 0.4, P = 0.001). Atherosclerotic burden was lower in the HIV group with more normal infarct-related arteries (47% vs. 13%, P = 0.005) but a higher degree of large thrombus burden (43% vs. 17%, P = 0.02). Stents were used to a similar degree in HIV and control patients (30% vs. 37%, P = 0.78) with more target lesion revascularization in the HIV group (56% vs. 0%, P = 0.008). Conclusion: Treatment-naïve HIV patients with ACS are younger and have fewer traditional risk factors than HIV-negative patients. HIV patients have less atherosclerotic but higher thrombotic burden which may imply a prothrombotic state in the pathogenesis of ACS in these patients.