Context: Discrete regulation of the uterine and placental vasculatures is an important feature of uteroplacental perfusion and pregnancy success because appropriate maternal/fetal exchange of nutrients and gases is crucial for normal fetal growth. Placental vasculature lacks autonomic innervation so tone is controlled by locally derived vasoactive factors. IGF-I, which is produced by the placenta, is critical for normal fetal growth and studies of animal vascular systems have shown that IGF-I regulates vasomotor tone. Objective: The objective of the study was to determine whether IGF-I directly alters human placental and myometrial arterial tone in vitro. Participants: Women with uncomplicated pregnancy delivering a singleton infant at term participated in the study. Setting: The study was conducted at university hospital laboratories. Main Outcome Measure(s): Comparison of arterial tension measured before and after exposure to IGF-I. Design: Placental and myometrial arteries were mounted on a wire myograph, exposed to the constrictor U46619 (10-10 to 10-5 M), returned to baseline tension, and then incubated with IGF-I (0-500 ng/ml) for various time points before performing a second dose-response curve to U46619. IGF-I receptor protein expression was assessed. Results: IGF-I did not acutely alter the response of placental arteries to U46619. Exposure of myometrial arteries to IGF-I caused a rightward shift of U46619 dose-response curves (P < 0.05); EC50 data were significantly increased at 30 (15.5 ± 2.8 vs. 133 ± 44 nM, before and after IGF treatment, respectively) and 60 min (10.9 ± 1.9 vs. 146 ± 47 nM). Placental and myometrial arteries had a similar IGF-I receptor expression profile. Conclusions: IGF-I acutely modulates the vasomotor tone of human myometrial, but not placental, arteries, suggesting that IGF-I regulates the delivery of maternal blood to the placenta.