Elevated blood levels of soluble urokinase receptor (suPAR) measured by ELISA decrease in human immunodeficiency virus-1 (HIV-1)-infected patients initiating highly active antiretroviral therapy (HAART). As the suPAR ELISA measures both three- and two-domain suPAR [suPAR(I-III), suPAR(II-III)] and suPAR(I-III)-ligand complexes, the amount by which the individual suPAR forms (suPAR(I-III), suPAR(II-III) and one-domain suPAR [suPAR(I)]) decrease in plasma in HIV-1-infected patients initiating HAART is unknown. Consequently, the objective of this study was to investigate HAART-induced changes in the individual plasma suPAR forms in HIV-1-infected patients. Plasma suPAR was measured by three time-resolved fluorescence immunoassays detecting suPAR(I-III), suPAR(I-III) + suPAR(II-III) and suPAR(I) in 29 treatment-naïve HIV-1-infected patients followed annually for 5 years after initiation of HAART and in 20 age- and gender-matched healthy individuals. In addition, plasma levels of the following inflammatory markers were also investigated: soluble tumour necrosis factor receptor (sTNFr)-II, TNF-alpha, interleukins (IL)-10, IL-6, IL-4, IL-2 and interferon (IFN)-gamma. In HIV-1-infected patients, plasma suPAR(I-III), suPAR(II-III) and suPAR(I) decreased within the first treatment year (all P < 0.05) and suPAR(I-III) and suPAR(II-III) remained above normal throughout follow-up (both P < 0.05). Plasma sTNFrII, IL-6, IFN-gamma and IL-10 also decreased during HAART (all P < 0.05). In HIV-1-infected patients, sTNFrII correlated with all suPAR forms before (all P < 0.01) and after 5 years HAART (all P < 0.001), whereas sTNFrII and suPAR did not correlate in healthy individuals. Intact and cleaved plasma suPAR decreased in HIV-1-infected patients initiating HAART but remained above normal. The positive correlation with sTNFrII suggests that the individual plasma suPAR forms are linked to immune activation in HIV-1 infection.