Purpose: The incidence of psychotic disorders varies in different geographical areas. As there have been no reports from Southern Italy, this study aimed to determine the incidence rate of first-episode psychosis in Palermo, Sicily. Methods: All patients, aged 18–65 years, presenting with a first episode of psychosis (FEP) (ICD-10 F20–29, F30–33) to mental health services in Palermo, were recorded over a 3-year period. Incidence rates of psychotic disorders and their 95% confidence intervals (95% CI) were estimated. Poisson regression was applied to estimate the differences in incidence rate ratio (IRR) by age, sex and migrant status. Results: Two hundred and four FEP participants were identified during the 3 years; 183 (89.7%, males n = 112) participants were native Italians and 21 were migrants (10.3%, males n = 14). The crude incidence of all psychoses was 15.9 (95% CI 13.7–18.1). As predicted, the risk of schizophrenia F20 was higher in males compared to females (adjusted IRR = 1.99, 95% CI 1.36–2.88) and in migrants compared to native Italians (adjusted IRR = 4.02, 95% CI 2.39–6.75). Conclusions: This study, the first from Sicily, confirms previous findings from Northern Italy that the risk of schizophrenia and other psychoses is much lower in Italian cities than those reported from cities in Northern Europe; the reasons for this disparity may provide important clues to the aetiology of psychosis.