We investigated the skin vasoreactivity to insulin in normal subjects and in treated non-insulin-dependent diabetes mellitus (NIDDM) patients. We measured cutaneous perfusion by laser-Doppler flowmetry (LDF) at rest and during skin cathodal iontophoresis (six pulses of 0.1 mA each for 20 s, with 40 s interval between stimulations) of insulin (0.1 ml Humulin R 100 IU/ml diluted 1/10 with of 0.9% saline solution) in 45 healthy subjects (HS), (25 males, 20 females, aged 45 ± 18 years), and in 15 treated NIDDM patients (13 males), aged 66 ± 8 years. Fifteen of the HS were used as controls. In these 15 sex- and age-matched HS and in the patients, we assessed also the skin postischemic hyperemia by LDF. In HS cutaneous blood flux response (CBF) to iontophoresis of insulin in saline (expressed as percent changes from baseline) was significantly higher than CBF response to iontophoresis of pure saline (maximum response: 360 ± 51% versus 172 ± 42%, respectively; P < 0.001, ANOVA for repeated measures). The maximum “net” CBF response to insulin (response to insulin minus response to saline) showed a negative correlation (r = -0.361; P < 0.01) with age in HS, and resulted significantly lower in the oldest than in the youngest HS (105 ± 40% versus 307 ± 45%, respectively; P < 0.01). No significant correlation was observed between the maximum CBF response to saline and the age of subjects. In NIDDM patients the “net” CBF response to insulin iontophoresis resulted significantly lower than in 15 sex- and age-matched control subjects (maximum response: -50 ± 89% versus 201 ± 81%, respectively; P < 0.001, ANOVA for repeated measures). No significant difference was observed between diabetics and controls, nor in basal perfusion (6.5 ± 1.3 IU versus 6.8 ± 1.7 IU, respectively) neither in the skin postischemic hyperemia (250 ±14% versus 258 ± 27%, respectively). These results confirm that insulin iontophoresis induces a skin vasodilatatory effect in normal subjects and show that this effect is reduced by aging and is absent in treated NIDDM patients. The local skin vasodilatatory effect induced by insulin seems to involve mechanisms different from those underlying the skin postischemic hyperemia.