Background Obese patients are more prone to post-injury multiple organ failure (MOF). Obesity pathophysiology includes an adipose-tissue-derived, renin-angiotensin-aldosterone system affecting inflammatory responses via leukocyte angiotensin receptors. We hypothesized that obese patients receiving pre-injury angiotensin-converting enzyme inhibitor (ACE) or angiotensin receptor blocker (ARB) therapy would have decreased MOF and differences in immune cell frequencies. Study Design We analyzed the Inflammation and the Host Response to Injury trauma-related database. Patients receiving pre-injury ACE or ARB were stratified as obese (BMI >30 kg/m2) or nonobese (BMI <30 kg/m2). Groups were age, sex, and Injury Severity Score matched against patients not receiving this therapy. Primary end points were Marshall Multiple Organ Dysfunction Score, Denver-2 Postinjury MOF Score, leukocyte markers on T cells, and monocytes measured by flow cytometry. Results We evaluated 1,932 patients. One hundred and ten were receiving pre-injury ACE/ARB; 94 patients had data available to calculate BMI. Obese patients receiving ACE/ARB showed maximum Marshall (5.83 ± 2.87) and Denver-2 (2.45 ± 2.32) scores similar to nonobese patients receiving or not receiving ACE/ARB, and obese patients not receiving ACE/ARB had significantly higher Marshall (6.49 ± 2.57; p = 0.009) and Denver-2 (3.33 ± 2.21; p = 0.006) scores. Leukocyte analysis suggested improved T-cell function and monocyte maturation in obese patients on ACE/ARB. Conclusions Obese patients receiving preinjury ACE/ARB therapy demonstrate post-injury MOF scores similar to nonobese patients; obese patients not receiving these medications have greater post-injury MOF. Leukocyte analysis demonstrates improved immune regulation. Modulation of the renin-angiotensin-aldosterone system pathway might represent a novel therapeutic target in severely injured obese patients.