This study aimed to determine the effect of highly active anti-retroviral therapy (HAART) and hepatitis C virus (HCV) co-infection on peripheral levels of interleukin (IL)-2, IL-10, IL-12 (p70), IL-18 and soluble tumour necrosis factor receptor type II (sTNFRII). Serum levels were monitored for a 1-year period in 25 patients infected with human immunodeficiency virus-1 (HIV-1) who were naive for HAART at the initiation of the study, and in four HIV-1-infected long-term non-progressors. Serum levels of both IL-18 and sTNFRII at baseline were significantly higher in HIV-1-infected patients than in controls. Baseline levels of IL-18 and sTNFRII were not significantly different in long-term non-progressors compared with the other patients. HCV co-infected patients had significantly higher levels of IL-18 and sTNFRII at each time-point compared with patients who were not co-infected with HCV. Irrespective of HCV status, response to HAART resulted in a significant decrease in the levels of both IL-18 and sTNFRII, particularly among patients who achieved HIV viral suppression, but the net decrease observed at the end of follow-up was lower in patients co-infected with HCV. No information was obtained from IL-2, IL-10 and IL-12 (p70) measurements. The data suggest that analysis of serum levels of IL-18 and sTNFRII may be a valuable tool for evaluating the response to HAART, and perhaps for assessing the degree of immune restoration achieved by HAART responders. The results also highlight the relevance of considering the HCV infection status of HIV-1-infected patients in order to avoid misinterpretation of IL-18 and sTNFRII measurements.