The aim of this study was to evaluate the acute effect of the transdermal administration of nicotine on insulin sensitivity in healthy individuals with and without family histories of type 2 diabetes mellitus (DM2) in the first branch. A randomized, double-blind, cross-over, placebo-controlled clinical trial with two parallel groups was carried out in 12 healthy individuals, six with a family history of diabetes and six without such family history. The volunteers were randomly assigned to administration of a nicotine or placebo patch and were crossed-over with a difference of at least 3 days between each patch. The insulin sensitivity was estimated by means of the total glucose metabolism, which was obtained with the euglycemic- hyperinsulinemic clamp technique before the randomized assignment and on the following day for the corresponding patch. At the beginning of each clamp technique procedure, the metabolic and hepatic profiles were measured. We found that the total glucose metabolism value was not modified with the administration of nicotine, either in the group with a family history of DM2 (3.9 +/- 1.0 vs. 3.5 +/- 0.7 mg/kg/min; p = 0.60) or in the group without such a family history (5.4 +/- 2.0 vs. 5.1 +/- 1.6 mg/kg/min; p = 0.34). The administration of placebo did not modify the insulin sensitivity in either group. We conclude that acute transdermal administration of nicotine did not modify insulin sensitivity in healthy individuals with or without a family history of DM2 in the first branch.