Karyomegalic tubulointerstitial nephritis is a rare disease of uncertain etiology, which leads to progressive renal failure. Here, we report on a 39-year-old patient who presented with asymptomatic progressive decline of renal function. Two sequential renal biopsies demonstrated chronic tubulointerstitial nephritis with bizarre and dramatic enlargement of proximal tubule epithelial cell nuclei - the hallmark of karyomegalic nephritis. Clinical and pathologic findings of this case are discussed in light of the available literature. The morphologic changes in this disease are highly characteristic if the pathologist is aware of this entity.