HIV infection is associated with chronic immune activation, subclinical inflammation, and an atherogenic metabolic profile. It remains controversial whether HIV infection is a risk factor for accelerated arteriosclerosis independent from the effects of antiretroviral drugs. We investigated whether aortic stiffness, an early marker of arteriosclerosis, is increased in HIV patients who were not under antiretroviral treatment. In 39 untreated HIV-infected patients and 78 individually matched age-, sex-, and blood pressure-matched HIV-uninfected control subjects, we determined aortic pulse wave velocity (PWV), a direct noninvasive measure of aortic stiffness, by tonometric method. Subjects with overt cardiovascular disease or major cardiovascular risk factors were excluded from the study. Prevalence of the metabolic syndrome was higher in HIV patients (18% versus 5%; P=0.025). HIV patients had a higher aortic PWV (7.5+/-1.4 versus 6.7+/-1.1 m.s(-1); P=0.001) than control subjects. Age, mean arterial pressure as a measure of distending pressure, and HIV infection (all P<0.05) independently predicted aortic PWV when a consistent number of cardiovascular risk factors was simultaneously controlled for. Among HIV-infected subjects, serum gamma-glutamyl transpeptidase concentration (beta=0.46; P=0.003) and mean arterial pressure (beta=0.32; P=0.03) were independent determinants of aortic PWV. In conclusion, aortic stiffness is increased in HIV-infected individuals who have never received antiretroviral therapy. PWV increases with increasing serum gamma-glutamyl transpeptidase concentration. Our data support the hypothesis that HIV infection is a risk factor for arteriosclerosis.