Systemic lupus erythematosus (SLE) is a severe complex rheumatic disease, but good estimate of its prevalence and risk factors is lacking in China. The aim of the study was to explore the prevalence of SLE and risk factors in rural areas of Anhui Province of China. Eleven counties were randomly selected in Anhui Province, and then, 15% of the villages in selected counties were randomly sampled as study sites. Patients with SLE were identified through two phases. Based on the cases identified, a population-based case-control study was designed to examine risk factors associated with SLE. A total of 1,253,832 individuals and identified 471 SLE cases were surveyed. Crude and age-standardized prevalence were estimated at 37.56 and 36.03 per 100,000 persons, respectively. Gender difference in the prevalence of SLE was significant (P = 4.62 × 10(-76)), and the age-standardized prevalence was 6.17 for males and 67.78 for females per 100,000 persons. The distribution of SLE prevalence was significant by age group (P = 1.78 × 10(-53)), and the peak prevalence was observed at 40-50 years. Multiple environmental factors were associated with SLE, including birth conditions, sweet food, cooking oil, taste, fruit consumption, sunlight exposure, quality of sleep, physical activities, drinking water, residence, negative life events, hepatitis B vaccine, age of menarche, and age at birth of first child (P < 0.05). Our large population-based epidemiological survey estimated the prevalence of SLE at 37.56 per 100,000 persons. Multiple environmental factors were associated with the development of SLE.