IMPORTANCE: Social determinants are important risk factors for the development of first-episode psychosis (FEP); their effects in rural areas are largely unknown. OBJECTIVE: To investigate neighborhood-level factors associated with FEP in a large, predominantly rural population-based cohort. DESIGN, SETTING, AND PARTICIPANTS: This study extracted data on referrals for treatment of potential FEP at 6 Early-Intervention Psychosis services from the Social Epidemiology of Psychoses in East Anglia naturalistic cohort study data set, which covered a population of more than 2 million people in a rural area in the East of England for a period of 3.5 years. All individuals aged 16 to 35 years who presented to Early-Intervention Psychosis services and met diagnostic criteria for first episodes of nonaffective psychoses and affective psychoses (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnostic codes F20-33) were included (n = 631). Persons whose disorders had an organic basis (diagnostic codes F06.X) and those meeting the criteria for substance-induced psychosis (diagnostic codes F1X.5) were excluded. We derived 4 neighborhood-level exposures from a routine population data set using exploratory factor analysis (racial/ethnic diversity, deprivation, urbanicity, and social isolation) and investigated intragroup racial/ethnic density and fragmentation. MAIN OUTCOMES AND MEASURES: Multilevel Poisson regression was performed to determine associations between incidence rates and neighborhood-level factors, after adjustment for individual factors. Results were reported as incidence rate ratios (IRRs). RESULTS: The study included 631 participants who met criteria for FEP and whose median age at first contact was 23.8 years (interquartile range, 19.6-27.6 years); 416 of 631 (65.9%) were male. Crude incidence of FEP was calculated as 31.2 per 100 000 person-years (95% CI, 28.9-33.7). Incidence varied significantly between neighborhoods after adjustment for age, sex, race/ethnicity, and socioeconomic status. For nonaffective psychoses, incidence was higher in neighborhoods that were more economically deprived (IRR, 1.13; 95% CI, 1.06-1.20) and socially isolated (IRR, 1.11; 95% CI, 1.04-1.19). It was lower in more racially/ethnically diverse neighborhoods (IRR, 0.94; 95% CI, 0.87-1.00). Higher intragroup racial/ethnic density (IRR, 0.97; 95% CI, 0.94-1.00) and lower intragroup racial/ethnic fragmentation (IRR, 0.98; 95% CI, 0.96-1.00) were associated with a reduced risk of affective psychosis. CONCLUSIONS AND RELEVANCE: Spatial variation in the incidence of nonaffective and affective psychotic disorders exists in rural areas. This suggests that the social environment contributes to psychosis risk across the rural-urban gradient.