We have previously described the prevalence of glomerulomegaly in biopsy specimens from Australian Aborigines with renal disease, a phenomenon documented in a number of other indigenous populations. Many of the biopsy specimens showed variable degrees of focal and segmental glomerulosclerosis (FSGS). Correlations between glomerular size and FSGS have been described in various animal models, as well as studies of humans. The aim of this study is to determine whether a relation exists between glomerular volume and severity of FSGS in biopsy specimens from Australian Aboriginals in the Northern Territory and Aboriginal inhabitants of the Tiwi Islands (Bathurst Island and Melville Island, Northern Territory, Australia). Consecutive clinical biopsy specimens were obtained from 78 non-Tiwi and 72 Tiwi Aboriginals. Glomerular volume was estimated using the stereological method of Weibel and Gomez. FSGS was graded from 0 to 4; 0 indicates no sclerosis and 4 indicates severe sclerosis. A biphasic relationship between glomerular size and severity of FSGS was identified. As the severity of FSGS increased from grade 0 to grade 3, glomerular size also increased. For both populations studied, glomeruli scored as grades 1, 2, and 3 were approximately 50% (P< 0.001), 65% (P< 0.001), and 100% (P< 0.001) larger than normal glomeruli, respectively. However, in glomeruli with grade 4 FSGS, glomerular size decreased to the size of normal glomeruli. These results show a biphasic relationship between severity of FSGS and glomerular size in Australian Aborigines.