Purpose: CD163 is a monocyte/macrophage-associated antigen which has recently been identified as a hemoglobin scavenger receptor and has also anti-inflammatory properties and an immunoregulatory role. This surface receptor undergoes ectodomain shedding upon an inflammatory stimulus, leading to increased fraction of soluble CD163 (sCD163). Hence, we hypothesized that the mechanical ventilation (MV) which is known to elicit inflammatory response may cause increased serum levels of sCD163 which can predict the outcome of patients from MV. Subjects and Methods: Thirty patients with acute respiratory distress aged >18 years who required MV were enrolled for the study. Serum levels of sCD163 were estimated using quantitative immunometric sandwich enzyme immunoassay technique from 3 mL of the venous blood sample which was collected immediately and at 24 h after the patient was connected to MV. On the basis of the outcome of the patient from MV, they were divided into two groups; survivors and nonsurvivors. Results: Out of the 30 patients, 18 patients survived and 12 patients expired. Serum levels of sCD163 were significantly increased in nonsurvivors when compared with survivors (P < 0.01) at 24 h after connecting to MV. sCD163 > 1020 ng/mL at 24 h of MV increases the probability of mortality by factor 6. An increase of sCD163 by 1 ng/mL significantly increases the relative probability of mortality by a factor of 1.0017 (95% confidence interval, 1.0004-1.0030, P = 0.0005). Conclusions: Elevated levels of sCD163 at 24 h of MV help in predicting the outcome of patients with acute respiratory failure from MV.