Despite low mortality rates, self-inflicted stab wounds (SISWs) can result in significant morbidity and often reflect underlying substance abuse and mental health disorders. This study aimed to characterize demographics, comorbidities, and outcomes seen in self-inflicted stabbings and compare these metrics to those seen in assault stabbings. A Level I trauma center registry was queried for patients with stab injuries between January 2010 and December 2015. Classification was based on whether injuries were SISWs or the result of assault stab wounds (ASWs). Demographic, injury, and outcome measures were recorded. Differences between genders, ethnicities, individuals with and without psychiatric comorbidities, and SISW and ASW patients were assessed. Within the SIWS cohort, no differences were found when comparing age, gender, or race, including need for operative intervention. However, patients with psychiatric histories were less likely to have a positive toxicology test on arrival than those without psychiatric histories (22% vs. 0%, P = 0.04). When compared with 460 ASW patients, SISW were older (41 vs. 35, P < 0.001), more likely to be white (92% vs. 64%, P < 0.001), more likely to have a psychiatric history (15% vs. 4%, P < 0.001), require operative intervention (65% vs. 50%, P = 0.008), and be discharged to a psychiatric facility (47% vs. 0.2%, P < 0.001). SISW patients have higher rates of psychiatric illness and an increased likelihood to require operative intervention as compared with ASW patients. This population demonstrates an acute need for both inpatient and outpatient psychiatric care with early involvement of multidisciplinary teams for treatment and discharge planning.