The objective of the study is to test whether circulating proteasomes are increased in burn patients and to assess whether possible alterations are associated with severity of injury, organ failure, and/or clinically relevant outcomes. In this study, plasma was obtained from burn patients on days 0 (admission, n = 50), 1 (n = 36), 3 (n = 35), 5 (n = 28), 7 (n=34), and 30 (n = 10) (controls: 40 volunteers). The 20S/26S proteasome levels were measured by enzyme-linked immunosorbent assay. Proteasome peptidase activity was assessed using a chymotryptic-like peptide substrate in combination with epoxomicin (specific proteasome inhibitor). Percentage of TBSA burned, presence of inhalation injury, development of sepsis/multiple organ failure, and sequential organ failure assessment scores were documented. On admission, plasma proteasome activity was higher in patients than in controls (P = .011). 26S proteasomes were not detectable. The 20S proteasome concentrations (median [25th/75th percentile]) peaked on day 0 (673 [399/1566] ng/mL; control: 195 [149/249] ng/mL, P < .001), gradually declined within 7 days, and fully returned to baseline at day 30 (116.5 [78/196] ng/mL). Elevated 20S proteasomes were associated with the presence of inhalation injury and correlated linearly with %TBSA in patients without inhalation injury. Initial 20S proteasome concentrations discriminated the presence of inhalation injury in patients with (sensitivity 0.88 and specificity 0.71) and without (sensitivity 0.83 and specificity 0.97) cutaneous burns but did not discriminate sepsis/multiple organ failure development or survival. Circulating 20S proteasome is a biomarker of tissue damage. The 20S proteasome plasma concentrations in patients with burns and/or inhalation injury are unlikely to predict outcomes but may be useful for the diagnosis of inhalation injury.