Previously, we reported an increase in soluble tumor necrosis factor-alpha receptor two (sTNF-R2) and soluble CD14 (sCD14) in the plasma of HIV-seropositive individuals with neurocognitive dysfunction compared to their cognitively intact counterparts. As intravenous drug use is not only a risk factor for HIV but also an immunomodulator, we sought to examine the effects of drug use on soluble markers of immune activation. These relationships were investigated in 25 patients with late stage HIV-1 disease. TNF-alpha, sTNF-R1, sTNFR2, and sCD14 were measured in patient plasma. These values were correlated with drug use and neurocognitive function. sTNF-R2 was significantly up-regulated in those patients who used opiates compared to those who did not. There was no difference in TNF-alpha, sTNF-R1, or sCD14 between the groups. Further, there was no connection between opiate use and neurocognitive dysfunction.