Acute renal failure developed in a 57-year-old woman who had Rosai-Dorfman disease diagnosed 1 year previously on a cervical lymph node. Organ imaging showed diffuse masses infiltrating both kidneys. The renal biopsy showed a lymphoplasmacytic and histiocytic process extensively replacing the parenchyma, which is in keeping with Rosai-Dorfman disease of the kidneys. However, the typical lymphophagocytic cells were lacking. This case illustrates that diagnosis of Rosai-Dorfman disease in renal biopsy can be very difficult, requiring both exclusion of many benign and malignant lesions and a high index of suspicion for this condition. In particular, lymphoma was excluded based on the mixed polyclonal composition of inflammatory cells and the absence of atypical lymphoid proliferation. The renal function partially recovered after a course of therapy combining VP-16 (etoposide) and dexamethasone and remained stable over 4-year follow-up. This report emphasizes the importance of early diagnosis and intervention to safeguard renal function in extensive Rosai-Dorfman disease.