Objective: Leptospirosis is a worldwide zoonosis caused by pathogenic Leptospira spp. The aim of this study was to report the incidence of leptospirosis from 1998 to 2012 in the state of São Paulo, Brazil to show the importance of human leptospirosis and to describe some epidemiological characteristics. Methods: From January 1998 to December 2012, sera from patients with suspected leptospirosis were analyzed. The microscopic agglutination test (MAT) was used for serological investigations and MLST, serotyping and PFGE methods for the identification of leptospires. The descriptive seasonal analysis was performed with Excel Microsoft version 2007. Pearson's correlation was used to assess the association between rainfall and the number of cases. Results: Among 22,795 serum samples, 2,430 cases of leptospirosis were laboratory confirmed, giving an average incidence rate of 1.35/100,000 inhabitants. Of these patients, 2,032 (83.62%) were male with a predominance in the age groups of 21-50 years. The highest incidence and rainfall were from December to April. There was correlation between the rainfall and the number of cases. Icterohaemorrhagiae was the predominant serogroup. Conclusions: This study shows that leptospirosis is a seasonal disease in São Paulo with most cases occurring during the rainy season, and thus, will continue to be a disease of public health importance.