Chronic kidney disease of unknown etiology (CKDu) is a major healthcare issue in Sri Lanka. This study included 125 consecutive patients with a diagnosis of CKDu undergoing renal biopsy at one hospital from 2008 to 2012. Associations between renal outcome parameters, epidemiological data, and histopathological findings were examined and regression models constructed based on univariate associations with outcome variables as serum creatinine >1.2 and stage of CKD >3. The mean patient age was 46.21 years (standard deviation = 11.64). A marked male predominance was noted. A positive family history of CKD was seen in 35.8%. Prominent histopathological features were glomerular sclerosis (94.8%), interstitial infiltration (76%) with lymphocytic infiltration, interstitial fibrosis (71.2%), and tubular atrophy (70.4%). Importantly, significant histological changes were seen in patients with early CKDu. For CKD stage >3 independent associations were: interstitial fibrosis [P = 0.005; odds ratio (OR) =0.153] and interstitial infiltrate (P = 0.030; OR = 0.2440. For serum creatinine >1.2, independent predictors were >50% glomerular sclerosis (P = 0.041; OR = 0.92), tubular atrophy (P = 0.034; OR = 0.171, and more than 40 residential life years (P = 0.009; OR = 9.229). Chronic tubulointerstitial nephritis (TIN) appears to be the predominant histopathological finding in patients with CKDu, with significant renal pathology established early on in the course of the disease. Interstitial infiltration appears to be an independent association of advancing CKD, CKDu, histopathology, histology, and TIN.