OBJECTIVE This study aimed to investigate quality of life and burden on caregivers in Spanish outpatients with schizophrenia, treated with different antipsychotics. METHODS Sociodemographic and clinical data were collected for 1865 patients diagnosed with schizophrenia. Patients answered the EuroQol-5D questionnaire and caregivers answered questionnaires assessing caregiver burden. Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression of Severity (CGI-S), and clinician's satisfaction were also recorded. The same data were also collected at months 3 and 6. RESULTS According to EQ-5D results, usual activities (29.6%) and anxiety/depression (31.1%) were the most relevant reported problems. Good overall scores (5-7) on EQ-5D were reported by 47/118 (39.8%) of risperidone long-acting injectable (LAI) patients compared to 52/218 (23.9%) for oral conventional antipsychotics, 51/194 (26.2%) for injectable conventional antipsychotics, and 332/1110 (29.9%) for oral atypical antipsychotics. Significant benefits of risperidone LAI vs. other types of antipsychotic were also found in caregiver burden and clinician-derived outcome measures. At months 3 and 6, retention was > 85%, and score on the EQ5D improved for the overall sample. CONCLUSIONS In Spanish patients with schizophrenia, activities of daily living and anxiety/depression were more relevant reported problems. Risperidone LAI was associated with better quality-of-life outcomes and lower caregiver burden compared to other types of antipsychotic.