Purpose <p>Approximately 27% of patients with an eating disorder (ED) present with comorbid non-suicidal self-injurious behaviors (NSSI). EDs comorbid with NSSI display worse eating psychopathology and overall psychological distress. This follow-up study aims to compare the clinical and psychopathological characteristics at the time of hospital admission and the long-term outcome of patients with and without comorbid NSSI.</p> Methods <p>73 adolescents affected with an ED were included in the study and divided into two groups depending on the comorbidity with NSSI. Clinical and anamnestic data, personality traits, social, emotional and behavioral functioning, and eating psychopathology were collected. A comparison was made between the NSSI group and the non-NSSI group on clinical and psychopathological characteristics. After a 5-year follow-up, participants were interviewed with a structured interview to investigate the history of AN and NSSI, and they completed questionnaires for the self-assessment.</p> Results <p>Specific personality traits like low Cooperativeness and low levels of Reward Dependence, greater impairment of behavioral and emotional functioning, and worse eating psychopathology characterized AN participants with NSSI. The 5-year outcome was less favorable in participants with a history of NSSI with a remission rate 77.7% in participants with AN alone and of 21% in participants with NSSI.</p> Conclusions <p>The differences between subgroups highlight the need to investigate NSSI at the initial clinical evaluation of adolescents who come to observation for an ED. Clinical and psychopathological characteristics of AN with comorbid NSSI require more intensive care and tailored therapeutic approaches to improve the long-term outcome, promoting recovery and improving quality of life.</p> <p><i>Level of Evidence</i> III: Evidence obtained from well-designed cohort or case–control analytic studies</p>