Objective. The ItalKid Project is a prospective, population-based registry that was started in 1990 with the aim of assessing the epidemiology of childhood chronic renal failure (CRF), describing the natural history of the disease, and identifying factors that influence its course. This article reports the epidemiologic results. Methods. Prevalent and incident cases of CRF in children and adolescents were identified throughout Italy (total population base: 16.8 million children) by regularly asking all of the pediatric hospitals and adult nephrology units potentially involved in caring for children with kidney disease to report all cases that meet the inclusion criteria and then to update the clinical information regarding all previously reported patients on an annual basis. The inclusion criteria were 1) creatinine clearance (Ccr; according to Schwartz’s formula) <75 mL/min/1.73m2 bsa (predialysis) and 2) an age of <20 years at the time of registration. Results. By December 31, 2000, 1197 patients (803 boys) had been registered. The mean incidence was 12.1 cases per million (range: 8.8–13.9), and the (point) prevalence was 74.7 per million of the age-related population. The mean age at registration was 6.9 ± 5.4 years, and the mean Ccr was 41.7 ± 20.5 mL/min/1.73 m2. The leading causes of CRF were hypodysplasia associated with urinary tract malformations (53.6%) and isolated hypodysplasia (13.9%), whereas glomerular disease accounted for as few as 6.8%. Hypodysplasia associated with primary vesicoureteral reflux (VUR) alone was responsible for as many as 25.8% of the cases, thus being the leading single cause with a female-to-male ratio of 1:3.2. The diagnosis of VUR was established early in life at an overall median age of 3 months (range: 0–180). However, the diagnosis was made significantly later among girls, whose median age at diagnosis was 9 months (range: 0–156; 95% confidence interval: 21.2–49.3) as against 2 months among boys (range: 0–180; 95% confidence interval: 10.9–21.2). As many as 23.6% of the registered patients had at least 1 severe associated disease (excluding urological abnormalities). A steep decline in renal survival occurred during puberty and early postpuberty, leading almost 70% of the patients to end-stage renal failure by the age of 20 years. When the population was subdivided on the basis of Ccr at the time of registration, the probability of kidney survival at 20 years of age was significantly different, being 63% in patients with mild renal failure (Ccr 51–75 mL/min), 30% in those with moderate renal failure (Ccr 25–50 mL/min), and 3% in those with severe renal failure (Ccr <25 mL/min). The incidence of renal replacement therapy was 7.3/y/100 patients, and the case-fatality rate on conservative treatment was 1.41%. Conclusions. This study provides important and recent epidemiologic information concerning CRF in children and adolescents: a mean annual incidence of 12.1 new patients per million of the age-related population with a very high proportion (57.6%) of hypodysplastic renal diseases with or without urinary tract malformation. By the age of 20 years, the cumulative probability of end-stage renal disease in the population as a whole was 68%. The probability of kidney survival sharply declined during puberty and early postpuberty. This is the first prospective evaluation of the incidence and outcome of CRF in children, including those with mild and moderate renal impairment.