BACKGROUND Karyomegalic nephropathy, first identified in 1974, represents an increasingly recognized, but perhaps underdiagnosed condition associated with interstitial nephritis. It undoubtedly leads to end-stage renal disease requiring renal support. RESULTS We present a series of six cases of karyomegalic nephropathy. The age at diagnosis was 9-51 years, median 33 years. Impaired renal function, proteinuria, and haematuria were present in the majority of cases. Non-specific elevated liver enzymes were present in three cases. Two patients died soon after transplantation from overwhelming respiratory sepsis. The classical histological features of large, abnormal hyperchromatic nuclei with irregular outlines within epithelial cells were present in renal epithelial cells. Abnormality of DNA ploidy distributions compared with age- and sex-matched controls, and characterized by the presence of significant numbers of cells with high ploidy values was present in cases but not in controls. Mitotic figures were absent. Proliferation markers, Ki-67 and proliferating cell nuclear antigen/cyclin were not significantly elevated in those cases examined. Human leukocyte antigen analysis did not support the clustering of A9 or B35, in the cases or their families. CONCLUSIONS The presence of significant renal impairment, positive urine sediment, abnormal liver enzymes, and early age of onset should alert one to the presence of karyomegalic nephropathy. It represents an underdiagnosed disorder with a high degree of ploidy indicative of karyotypic abnormality.