Erdheim-Chester disease (ECD) is a rare form of systemic non-Langerhans cell histiocytosis with characteristic bone involvement. However, extraskeletal involvement occurs in approximately half of the patients. Because of its protean findings, the diagnosis of ECD is often delayed; thus, a clinical suspicion may prompt specific imaging studies to recognize suggestive signs of organ involvement. In this study, a case of a patient with ECD with representative progressive multisystemic involvement has been reported; although the final diagnosis was confirmed by histologic analysis, imaging studies with almost pathognomonic findings guided the diagnostic process and prompted different therapeutic approaches according to the localization of the disease.