BACKGROUND: The condition that came to be known as nephrogenic systemic fibrosis (NSF) was first reported in 2000 and, in 2001, was termed "nephrogenic fibrosing dermopathy." Since then, NSF has been the subject of a wide-ranging multidisciplinary medical investigation that has proven an indisputable link to renal disease and a compelling association with the increasing use of gadolinium-containing magnetic resonance imaging contrast agents in the renally impaired. OBJECTIVE: Although precise causation and risk factors continue to be elucidated, the need for reproducible prospective epidemiologic data demands clear and objective criteria for the diagnosis of NSF. METHODS: Experts in NSF diagnosis used their experience and the resources of the Yale International NSF Registry to develop a clinicopathological diagnostic system for NSF. RESULTS: A consensus scoring system incorporating a clinical and histopathological atlas was devised to guide and standardize the evaluation and diagnosis of NSF. LIMITATIONS: There is no laboratory test that can be used as a gold standard to diagnose NSF. To overcome this, we relied on classic clinicopathological presentations, published sources, and consensus clinical expertise to ensure the integrity of the study population. CONCLUSION: The clinicopathological definition of NSF provides guidance to physicians for the evaluation and diagnosis of NSF. Clinical, laboratory, and histopathological features comprise a schema that excludes conditions mimicking NSF while facilitating its reproducible and accurate diagnosis, even among physicians with little prior clinical experience with this entity. This definition can serve as a working diagnostic standard for future research and as the basis for adjudicating borderline cases. All rights reserved.