Diabetes mellitus (DM) is an independent risk factor for the development of kidney disease. This study assesses the prevalence and determinants of asymptomatic kidney disease in individuals with DM attending health facilities in OR Tambo district, Eastern Cape, South Africa.In this cross-sectional analysis, medical data of 327 individuals receiving care for DM in primary health care centers in OR Tambo district, Eastern Cape between June and November 2013 were reviewed. Significant kidney disease was defined as estimated glomerular filtration rate less than 60 mL/min/1.73 m in accordance with the guidelines of the Society of Endocrinology, Metabolism and Diabetes of South Africa (2017).One-quarter of the 327 participants (n = 80) had significant kidney disease. Female sex [odds ratio (OR) = 5.2; 95% confidence interval (95% CI) 1.2-23.5], never used alcohol (OR = 13.4; 95% CI 2.5-72.1), hypertension (OR = 16.2; 95% CI 2.0-130.0), triglyceride (TG)/high-density lipoprotein (HDL) ratio (OR = 1.2; 95% CI 1.0-1.5), current smoker (OR = 1127.9; 95% CI 162.9-7808.9), former smoker (OR = 13.3; 95% CI 4.1-41.4), and longer duration of diabetes (OR = 4.6; 95% CI 1.6-13.0) were the independent determinants of significant kidney disease among the participants. A significant dose--effect relationship exists between renal disease and smoking status (P < .0001), duration of DM (P < .001), glycemic status (P = .025), and body mass index (P = .003).There is a high rate of undiagnosed kidney disease in this setting, which was independently associated with female sex and presence of other cardiovascular risk factors. Strategic interventions targeting screening and monitoring of renal functions in individuals with DM are urgently needed in this region.