No clear association between human disease and TT virus (TTV) has been documented. A possible pathogenic role of TTV was investigated in patients infected with human immunodeficiency virus (HIV). TTV serum concentrations were estimated in 185 HIV-infected patients by dilution polymerase chain reaction. Of these, 149 (76%) were TTV-positive, compared with 18 (7%) of 252 Danish blood donors (P < .001). Of the HIV-infected patients who were TTV-positive, 72 (51%) had high TTV viremia (⩾5 times the highest concentration observed among blood donors, i.e., ⩾3.5 × 105 TTV/mL of serum). High TTV viremia was associated with decreased survival (P < .001; relative hazard [RH], 2.0). There was a correlation between lower CD4+ T cell counts and higher TTV titers (P < .01). In a Cox regression model, CD4+ T cell count (P < .001), age (P < .001), HIV viral load (P < .001), β2 microglobulin (P < .02), and high TTV viremia (P < .01; RH, 1.9) were independent predictors of survival. TTV is suspected to be an opportunistic pathogen with an independent influence on HIV progression.