The role of glucose‐6‐phosphatase (G6Pase) in postreceptional glucose handling in non‐insulin dependent diabetics (NIDDs) was investigated by comparing the enzyme values in diagnostic liver biopsy samples with fasting blood glucose (BG), immunoreactive insulin (IRI) and plasma antipyrine half‐life (T/2). The NIDDs, treated with sulphonylureas, had elevated serum aminotransferase and alkaline phosphatase values associated with fatty liver with or without fibrosis. G6Pase activity was reduced in the NIDDs compared with subjects who had undergone gallstone surgery (p<0.001), insulin dependent diabetics (p<0.001), and age‐ and sex‐matched non‐diabetics (p<0.001). G6Pase was inversely related to BG and antipyrine T/2, but not to IRI or conventional liver function tests. Therapy with phenobarbital and medroxyprogesterone acetate, known inducers, increased G6Pase activity, shortened antipyrine T/2, reduced BG and did not alter IRI, in four NIDDs. Low liver G6Pase activity in NIDDs may hence be one factor underlying the impaired glycemic control.