Objective: The purpose of this work was to study whether there are differences in plasma proinsulin levels and proinsulin-to-speci®c insulin ratio in the offspring of patients with different phenotypes of type II diabetes. Design: Eleven glucose-tolerant offspring of type II diabetic patients with de®cient insulin secretion phenotype (IS group), nine glucose-tolerant offspring of patients with insulin-resistant phenotype (IR group), and fourteen healthy control subjects without a family history of diabetes were studied. Methods: Plasma speci®c insulin, plasma proinsulin, and plasma C-peptide levels were measured during a 2-h oral glucose tolerance test and during hyperglycemic clamp. Results: Plasma proinsulin levels during the oral glucose tolerance test and the hyperglycemic clamp did not differ among the study groups. The IR group had a lower fasting plasma proinsulin-to-speci®c insulin ratio (10.3 6 1.7%) than the control group (15.4 6 1.4%; P < 0.05) and the IS group (18.6 6 2.7%; P < 0.05). Furthermore, the IR group had lower plasma proinsulin-to-speci®c insulin ratio at 30, 60 and 90 min after the oral glucose load than the IS group. However, there were no signi®cant differences in proinsulin-to-C-peptide ratio during the oral glucose tolerance test among the study groups. In stepwise multiple regression analysis, hepatic speci®c insulin extraction in the fasting state (b 0.65; P < 0.001) and fasting blood glucose (b 0.32; P < 0.05) together explained 52% of the variation in fasting plasma proinsulin-to-speci®c insulin ratio. Conclusions: Hyperproinsulinemia is not a characteristic ®nding in glucose-tolerant offspring of type II diabetic probands with de®cient insulin secretion or insulin-resistant phenotype. The differences in proinsulin-to-speci®c insulin ratios were most likely explained by different hepatic extraction among the study groups.