The inactivation of digoxin by conversion to reduced metabolites (digoxin reduction products, or DRP), a function of the anaerobic gut flora, was studied in normal volunteers from southern India and the United States. Digoxin was metabolised to DRP by 28 (13.7%) of 204 healthy south Indians in contrast to 67 (36.0%) of 186 New Yorkers (p less than 1 X 10(-6)). Only 1.0% of Indians compared with 14.0% of Americans excreted large amounts of metabolites (greater than 40% DRP) in the urine (p less than 1 X 10(-5)). Of 104 urban Indians, 23 (22.1%) were metabolisers, in contrast with five of 100 rural villagers (p less than 0.001). Within the urban group, digoxin metabolism correlated with education, frequency of animal protein intake, and most significantly, personal income. Organisms capable of reducing digoxin in vitro were found with similar frequencies in stool cultures from Indians and Americans. In the cultures of some subjects, DRP production was inhibited at lower dilutions but expressed at higher dilutions. We conclude that variations in drug metabolism between population groups may result from differences in the metabolic activity of the anaerobic gut flora probably mediated by environmentally determined factors.