Introductionleptospirosis is an emerging zoonosis of global importance. In South Africa, the infection is an underreported public health concern, with limited information on its incidence and distribution. This study investigated the incidence of human leptospirosis in Western Cape Province (WCP) between 2010 and 2019, and compared the incidence based on seasonal and demographic factors.Methodsa retrospective study was conducted with data on leptospirosis diagnoses in WCP obtained from the National Health Laboratory Services. With the provincial population sizes as the denominator, incidence of leptospirosis was estimated and expressed as cases per 100,000 population. Negative binomial regression was used to estimate the effect of sex, season, and year on the incidence of leptospirosis.Resultstwo hundred and fifty-four (254) cases of leptospirosis were reported between 2010 and 2019, with the highest number of cases being in 2015 and the annual incidence ranged between 0.15 and 0.66/100,000 population. Males had a higher incidence compared to females (0.55 vs. 0.25/ 100,000 population; incidence rate ratio (IRR) 2.2, 95% CI: 1.66,3.03). The 18-44 age cohort had the highest average incidence (0.56/100,000 population), while the ≤17 age cohort had the lowest incidence (0.07/100,000 population). The 18-44 (IRR 8.0, 95% CI: 4.65,15.15) and ≥45 (IRR 7.4, 95% CI: 4.17,14.17) age cohorts were more at risk of infection compared to ≤17 age cohort.Conclusionleptospirosis is an important zoonosis in WCP disproportionately affecting males and the productive age demographic groups. These findings should enhance targeted prevention and provoke further investigation on the importance of environmental and socioeconomic factors on leptospirosis burden.