Background: Health professionals in Sri Lanka have noticed high occurrence of a new form of chronic kidney disease of unknown etiology (CKD-U) in farmers of North Central Region (NCR). The aim of the study is to identify the epidemiological characteristics and risk factors related to agriculture practices in the development of CKD-U by using cohort and case control studies. Methods: Basic demographic information were collected from 11322 CKD-U patients in community renal clinics for the cohort study. For the case control study potential agricultural risk factors as involvement in agricultural activities with cultivating land area, hiring labour for agricultural activities, protective status against agrochemicals were collected from recently diagnosed, biopsy proven 274 CKD-U patients and 274 healthy age and sex matched controls selected on a random basis. Drinking water source, smoking, alcohol consumption, family history of CKD-U, history of snake bite and malaria were also collected. The relative risk of each factor was compared in terms of Odds ratios (OR) and 95% confidence intervals (CI) by applying the conditional logistic regression model. Results: The cohort study revealed that the mean age of the patients was 54 years and males were mostly affected than females (2.4:1) and 90% of the patients are farmers. The male to female ratio of the case control study was 2:1 and Involvement in agricultural activities greater than two hectares (OR3.415), low protective measures against agrochemicals (OR-1.966), and cultivating lands without hiring labour (OR-4.383) were identified as significant risk factors for CKD-U. In addition to the agricultural activities smoking (OR-2.951) and family history of CKD-U (OR-2.809), drinking water from shallow wells (OR-2.050) and history of snake bite (OR-1.602) were identified as other life style related risk factors. Conclusion: Male farmers over the age of 35 years have a strong occupational risk for CKD-U. Intense agricultural activities are significantly related for CKD-U. Low levels of protective measures in the agrochemical usage indicate the need to educate the farmers on safe agrochemical usage.