Macrophages play important roles during human immunodeficiency virus (HIV) infection, reflected by changes in macrophage-activation biomarker soluble CD163 (sCD163). Here, we present data on the novel macrophage-activation biomarker soluble mannose receptor/CD206 (sCD206) in HIV infection. We investigated sCD206 blood levels at baseline and follow-up with/without antiretroviral therapy (ART), in 212 patients with HIV type 1 (HIV-1), HIV type 2 (HIV-2), or dual infection. At baseline, there was no difference in sCD206 level between HIV types, and sCD206 was unchanged at follow-up without ART. However, in contrast to sCD163, sCD206 levels decreased significantly for both HIV-1 and HIV-2, but not for HIV-1/2 patients, during ART. Further investigations are needed to establish sCD206 as a biomarker in HIV infection.