Medically serious suicide attempts (MSSA) represent a subgroup of clinically heterogeneous suicidal behaviors very close to suicides. Personality disorders (PD) are highly prevalent among them, together with affective and substance use disorders. However, few studies have specifically analyzed the role of PD in MSSA. These suicide attempts (SA) are usually followed by longer hospitalization periods and may result in severe physical and psychological consequences. The aim of this study is to compare the profile of MSSA patients with and without PD. MSSA were defined according to Beautrais ‘criteria, but had to remain hospitalized ≥48 h. Overall, 168 patients from two public hospitals in Barcelona were evaluated during a three-year period. Mean hospital stay was 23.68 (standard deviation (SD) = 41.14) days. Patients with PD (n = 69) were more likely to be younger, female, make the first and the most serious SA at a younger age, reported recent stressful life-events and more frequently had previous suicide attempts compared to those without PD. However, no differences were found with regards to comorbid diagnoses, current clinical status, features of the attempt, or their impulsivity and hopelessness scores. Therefore, focusing on the subjective, qualitative experiences related to MSSA among PD patients may increase understanding of the reasons contributing to these attempts in order to improve prevention strategies in the future.