Introduction: Cyclic adenosine monophosphate plays an important role in peripheral chemoreflex function in animals. We tested the hypothesis that the phosphodiesterase inhibitor and inotropic medication, enoximone, increases peripheral chemoreflex function in humans. Methods: We included 15 healthy young men in a single-blind, randomized, placebo-controlled cross-over study. We measured ventilatory, MSNA, and hemodynamic responses to 5 minutes of isocapnic hypoxia, 5 minutes of hyperoxic hypercapnia, and 3 minutes of isometric handgrip exercise, after enoximone and placebo administration at a week’s interval. Results: Enoximone increased cardiac output by 120 ± 3.7% from baseline (p<0.001). It also increased the ventilatory response to acute hypoxia (13.6 ± 1 vs.11.2 ± 0.7L/min at the fifth minute of hypoxia, p=0.03 by ANOVA, enoximone vs. placebo, respectively). Despite a larger minute ventilation and a smaller decrease in oxygen desaturation (83 ± 1 vs.79 ± 2%, p=0.003), the MSNA response to hypoxia was similar between enoximone and placebo (123 ± 6 vs.117 ± 6%, p=0.28). In multivariate regression analyses enoximone enhanced the ventilatory (p<0.001) and sympathetic responses to isocapnic hypoxia. Hyperoxic hypercapnia and isometric handgrip responses were not different between enoximone and placebo (p=0.13). Conclusion: Enoximone increases modestly the chemoreflex responses to isocapnic hypoxia. Moreover, this effect is specific for the peripheral chemoreflex, as central chemoreflex and isometric handgrip responses were not altered by enoximone.