The aim of the study was to evaluate the effectiveness and tolerability of doses of paliperidone palmitate (PP) of 175 mgEq and over/28 days in patients with severe schizophrenia [Clinical Global Impression-Severity scale (CGI-S)>= 5] and their retention in treatment. A 36-month prospective, observational study was carried out of patients with severe schizophrenia who were treated with 175mg and over every 28 days of PP to achieve clinical stabilization (N=30). Assessment included CGI-S, WHO Disability Assessment Schedule, Camberwell Assessment of Need, and Medication Adherence Report Scale. Laboratory tests, weight, side effects, reasons for discharge, and hospital admissions were measured. The average dose of PP was 228.7 (11.9) mgEq/28 days. There was one discharge because of side effects. Weight and prolactin levels decreased. After 3 years, CGI-S (P<0.01), Camberwell Assessment of Need (P<0.01), and WHO Disability Assessment Schedule in the four areas (P<0.05) decreased. The Medication Adherence Report Scale increased (P<0.001). There were fewer hospital admissions (P<0.001). Retention in treatment after 36 months was 90%. Tolerability of 175 mgEq/28 days and over of PP was very good, being useful in improving treatment adherence in severely ill patients and helping in this way to achieve clinical stabilization and better social functioning. These patients were clozapine candidates; thus, high doses of PP could be an alternative for them. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.