Subjects with a patent foramen ovale (PFO) have blunted ventilatory acclimatization to high altitude, compared to subjects without PFO. The blunted response observed could be due to differences in central and/or peripheral respiratory chemoreflexes. We hypothesized that compared to subjects without a PFO (PFO-), subjects with a PFO (PFO+) would have blunted ventilatory responses to acute hypoxia and hypercapnia. Sixteen PFO+ subjects (9 female) and fifteen PFO- subjects (8 female) completed four 20-minute trials on the same day: 1) normoxic hypercapnia (NH), 2) hyperoxic hypercapnia (HH), 3) isocapnic hypoxia (IH), and 4) poikilocapnic hypoxia (PH). Hypercapnic trials were completed prior to the hypoxic trials, the order of the hypercapnic (NH & HH) and hypoxic (IH & PH) trials were randomized, and trials were separated by ≥40 minutes. During the NH trials, but not the HH trials, PFO+ subjects had a blunted hypercapnic ventilatory response compared to PFO- subjects (1.41 ± 0.46 L min-1 mmHg-1 vs. 1.98 ± 0.71 L min-1 mmHg-1, p = 0.02). There were no differences between the PFO+ and PFO- subjects with respect to the acute hypoxic ventilatory response during IH and PH trials. Hypoxic ventilatory depression was similar between PFO+ and PFO- subjects during IH. These data suggest that compared to PFO- subjects, PFO+ subjects have normal ventilatory chemosensitivity to acute hypoxia but blunted ventilatory chemosensitivity to carbon dioxide, possibly due to reduced carbon dioxide sensitivity of either the central and/or the peripheral chemoreceptors.