The Personality Inventory for DSM-5 (PID-5) is a questionnaire developed to assess the five domains represented in the alternative model for personality disorders proposed in Section III of the DSM-5. This study examined the ability of the PID-5 to distinguish between different mental disorders compared to a questionnaire measure of the five-factor model (FFM) of normative personality. The study included the administration of the PID-5 and Revised NEO Personality Inventory (NEO PI-R), a measure of the FFM, to treatment-seeking individuals with Depressive, Bipolar, Psychotic, and Alcohol Use Disorders (AUD). Diagnostic groups were compared at the domain level of PID-5 and NEO PI-R, with sex and age as covariates. The main findings on the PID-5 included higher Detachment scores for Bipolar and Depressive Disorders than Psychotic and AUDs, lower Psychoticism/higher Disinhibition scores for the AUD group compared to all other groups, and lower Negative Affect for the Psychotic Disorders versus AUD group. On the NEO PI-R, the AUD diagnostic group was associated with lower Conscientiousness and Agreeableness scores compared to all other groups, and lower Neuroticism scores than the Bipolar and Depressive groups. Group pairwise comparisons did not appear to show many differences between the PID-5 and NEO PI-R. The results suggest that the alternative DSM-5 model for personality disorders may have clinical utility in distinguishing personality profiles between diagnostic groups. These findings emphasize the importance of additional research on the capacity of maladaptive personality to contribute to the assessment of differential diagnoses.