SummarySerum concentrations of soluble tumor necrosis factor receptors (sTNF-Rs) were measured in 61 human immunodeficiency virus (HIV)-infected individuals. Thirty-five percent of these had increased serum concentrations of sTNF-R type I (p55) (sTNF-R55) and 82% had increased concentrations of sTNF-R type II (p75) (sTNF-R75). The extent of the increase of sTNF-R75 was greater in more advanced HIV infection (p= 0.046) as it was measured by dividing the 61 individuals into two groups according to the median of the CD4+T-cell count. However, the increase in concentrations of sTNF-R55 in the group with a CD4+T-cell count below the median was only moderate and did not reach statistical significance. A strong correlation was found between sTNF-R75 and the soluble immune activation markers β2-microglobulin (rs= 0.74,p< 0.0001) and urinary neopterin (rs= 0.67,p< 0.0001), and a less strong correlation was found with interferon-γ (rs= 0.51,p= 0.0001). The correlations observed for sTNF-R55 were also significant but were always weaker than that of sTNF-R75. A weak inverse correlation was found between the number of CD4+T cells and sTNF-R75 (rs= −0.33,p= 0.012), but no such correlation was observed with sTNF-R55. Our findings suggest that increased concentrations of serum sTNF-Rs in HIV infection are linked to immune activation, in which synergistic actions of interferon-γ and the TNF-α system are likely to play an important role.