OBJECTIVES: To assess adherence, persistence, costs and Health-Related-Quality-of-Life (HRQoL) in patients undergoing antipsychotic treatment. METHODS: A naturalistic, prospective cohort study, named COMETA, was conducted in 2006-2008. Subjects aged 18-40 years, diagnosed with schizophrenia or schizophreniform disorder ≤10 years before, were enrolled in 86 psychiatric centres throughout Italy and followed-up for a target period of 52 weeks. Data on socio-demographic, clinical status, adherence, HRQoL, resources consumption were collected (societal perspective adopted to estimate costs). RESULTS: A total of 637 valid patients (mean±SD age=30.9±5.9, 65.0% male) were enrolled and followed-up to 63.9 weeks. At enrolment, the Positive-and-Negative-Syndrome-Scale (PANSS) mean±SD score was 86.6±27.4, the Clinical-Global-Impression-Severity (CGI-S) mean±SD score was 4.3±1.1, the Global-Assessment-of-Functioning (GAF) mean±SD score was 54.1±13.8. With EQ-5D 68.8% of patients reported moderate/severe anxiety/depression, 52.7% reported problems with usual activities, 37.8% reported pain/discomfort, 21.4% had problems with mobility, 16.7% problems with self-care, VAS mean±SD=63.5±17.9. SF-36-PCS mean±SD=47.5±9.3, SF-36-MCS mean±SD=39.0±9.6. During 90 days before enrolment, 1.9% patients did not take any antipsychotic drug, while 27% took 2-5 different drugs. The Drug-Inventory-Attitude (DAI-30) mean±SD score, assessing the patients’ subjective attitude toward antipsychotic therapy, was 43.4±5.0. Physicians reported that 71.1% patients always took the prescribed antipsychotic therapy. Eighty-five percent of medical costs occurring 90 days before enrolment were: €114.00/patient-month for psychotherapy, €105.75/patient-month for hospitalizations (€89.49€ for relapse), €86.37/patient-month for antipsychotics, €13.74 for concomitant drugs. The patients persisted to treatment with oral typical, atypical or long acting/depot drugs on average 53.9 weeks. During the follow-up, psychotherapy cost was 100.03€/patient-month, hospitalizations cost €57.26/patient-month, antipsychotic drug therapy cost €126.10, concomitant therapy cost €16.47/patient-month. At the end of follow-up the patients’ clinical status, HRQoL and attitude toward treatment was on average improved. CONCLUSIONS: Increase of adherence and persistence toward antipsychotic treatment is a primary goal to be reached for the improvement of well being in schizophrenic patients and for making more efficient investments.