BACKGROUND: HIV infection is associated with an increased risk of coronary artery disease, but the contribution of inflammation versus antiretroviral drugs is not well understood. Fibrinogen is an inflammatory factor associated with atherosclerosis. METHODS: A total of 1131 HIV-infected patients and 281 controls [from the Coronary Artery Risk Development in Young Adults (CARDIA) study, a population-based study of cardiovascular risk assessment] in the Study of Fat Redistribution and Metabolic Change in HIV infection (FRAM) had plasma fibrinogen levels measured. Multivariable linear regression identified factors associated with fibrinogen. RESULTS: HIV-infected patients had higher levels of fibrinogen compared with controls (males: 25 mg/dl higher, P = 0.006; females: 21 mg/dl higher, P = 0.39). Among HIV-infected persons, median levels of fibrinogen were 11% higher in patients currently using any protease inhibitor (PI) compared with those not using a PI (P < 0.0001). The strongest univariate associations were with the individual PIs, ritonavir and indinavir. Patients taking indinavir boosted with ritonavir had median fibrinogen levels 8% higher than those on indinavir alone (P = 0.049). Lower levels of fibrinogen were seen in those HIV-infected patients currently using any nonnucleoside reverse transcriptase inhibitor (NNRTI) compared to those not using an NNRTI (nevirapine -14.4%, P < 0.0001; efavirenz -7%, P = 0.0002). The associations of ritonavir, indinavir, efavirenz and nevirapine with fibrinogen levels persisted after multivariable analysis and were independent of other antiretroviral use. CONCLUSION: Protease inhibitor use is associated with elevated fibrinogen levels which may contribute to increased risk of atherosclerosis in HIV-infected patients. Conversely, NNRTI use is associated with lower fibrinogen levels which may decrease risk of atherosclerosis. © 2008 Lippincott Williams & Wilkins, Inc.