Mid regional pro-adrenomedullin (MR-proADM) has been used as a marker of sepsis, but its dynamics and role in a burn injury setting has not been tested. In a prospective observational study, we included 42 consecutive patients with >15% TBSA. Daily blood specimens collected over the initial 20 days of treatment were submitted for laboratory analysis of MR-proADM and procalcitonin (PCT) via immunoluminometric sandwich assay (Kryptor, BRAHMS, Berlin, Germany). In patients with an absence of sepsis, an initial increase in MR-proADM and PCT levels was noted post-burn injury, peaking on the second day postadmission and thereafter demonstrated a continued decline in MR-proADM and PCT levels. In those patients who went on to develop sepsis (n = 27, 64.3%), the levels of MR-proADM and PCT were significantly higher (P < .001) on days categorized as septic, than on days categorized as nonseptic. The increase in PCT levels was noted on the first day to be categorized as septic. In contrast, the MR-proADM levels demonstrated an increase one day earlier. The optimal relationship between the specificity and sensitivity of MR-proADM and PCT for the detection of sepsis was an increase of 31% and at least 0.015 nmol/L (area under curve 0.76) or of >39% and at least 0.15 µg/L (area under the curve 0.83), respectively. Burn injury is associated with increased levels of MR-proADM. Subsequent increases may be considered as diagnostic of sepsis onset. In this context, PCT displayed higher specificity and sensitivity, while MR-proADM may be more suitable for the early recognition of sepsis (ClinicalTrials.gov number, NCT01055587).