Introduction: Investigations on predictors of real-world functioning were mainly performed in patients with schizophrenia, while fewer studies have been conducted in other psychiatric disorders. Objective: Our objective was to identify clinical, socio-demographic, and illness-related predictors of real-world functioning during 12 months of standard treatments in outpatients with different diagnoses. Methods: Outpatients (n = 1019) with schizophrenia (SZ), major depressive disorder (MDD), bipolar disorder (BD), and borderline personality disorder (BPD) were evaluated with the following tools: SCID-5-CV and SCID-5-PD, CGI-S, SAT-P, DAI-10, and PSP. Change of PSP (ΔPSP) between baseline and 12 months was used as the dependent variable in multiple regression analysis. Results: Higher PSP score at baseline and the achievement of main milestones predicted better functioning after follow-up in all subgroups of patients, with the exception of BD. In the total sample, ΔPSP was related to age of onset, treatments, and quality of life, and inversely related to psychiatric anamnesis, antidepressants, and global symptoms. In SZ, ΔPSP was related to adherence and quality of life. In MDD, ΔPSP was related to psychotherapy and quality of life, and inversely related to antidepressants and global symptoms. In BD, ΔPSP was related to age of onset, antipsychotics, and quality of life, while it was inversely related to psychiatric anamnesis. In BPD, antipsychotics, mood stabilizers, psychotherapy, and quality of life were directly related to ΔPSP, while suicidal attempts and global symptoms had an inverse relation. Conclusions: Several socio-demographic and illness-related variables predicted improvement of real-world functioning, besides psychopathology and severity of the disease.