Dipeptidyl peptidase-3 (DPP3) is a metallopeptidase which cleaves bioactive peptides, notably angiotensin II, and is involved in inflammation regulation. DPP3 has been proposed to be a myocardial depressant factor and to be involved in circulatory failure in acute illnesses, possibly due to angiotensin II cleavage. In this study, we evaluated the association between plasmatic DPP3 level and outcome (mortality and hemodynamic failure) in severely ill burn patients. In this biomarker analysis of a prospective cohort study, we included severely ill adult burn patients in two tertiary burn intensive care units. DPP3 was measured at admission (DPP3 ) and 3 days after. The primary endpoint was 90-day mortality. Secondary endpoints were hemodynamic failure and acute kidney injury (AKI). One hundred and eleven consecutive patients were enrolled. The median age was 48 (32.5-63) years, with a median total body surface area burned of 35% (25-53.5) and Abbreviated Burn Severity Index (ABSI) of 8 (7-11). Ninety-day mortality was 32%. The median DPP3 was significantly higher in non-survivors versus survivors (53.3 ng/mL IQR 28.8-103.5 versus 27.1 ng/mL IQR 19.4-38.9; p < 0.0001). Patients with a sustained elevated DPP3 had an increased risk of death compared to patients with high DPP3 but decreased levels on day 3. Patients with circulatory failure had higher DPP3 (39.2 ng/mL IQR 25.9-76.1 versus 28.4 ng/mL IQR 19.8-39.6; p = 0.001) as well as patients with AKI (49.7 ng/mL IQR 30.3-87.3 versus 27.6 ng/mL IQR 19.4-41.4; p = 0.001). DPP3 added prognostic value on top of ABSI (added chi 12.2, p = 0.0005), Sequential Organ Failure Assessment (SOFA) score at admission (added chi 4.9, p = 0.0268), and plasma lactate at admission (added chi 6.9, p = 0.0086) to predict circulatory failure within the first 48 h. Plasma DPP3 concentration at admission was associated with an increased risk of death, circulatory failure, and AKI in severely burned patients. Whether DPP3 plasma levels could identify patients who would respond to alternative hemodynamic support strategies, such as intravenous angiotensin II, should be explored.