Hypoxia increases the heart rate (HR) response to exercise but the mechanism(s) remain unclear. We tested the hypothesis that the tachycardic effect of hypoxia persists during separate but not combined inhibition of β-adrenergic and muscarinic receptors. Nine subjects performed incremental exercise to exhaustion in normoxia and hypoxia (FIO2 = 12%) after intravenous administration of either i) no drugs (CONT), ii) propranolol (PROP), iii) glycopyrrolate (GLYC), or iv) PROP and GLYC (PROP+GLYC). HR increased with exercise in all drug conditions (p < 0.001) but was always higher at a given workload in hypoxia than in normoxia (p < 0.001). Averaged over all workloads the difference between hypoxia and normoxia was 19.8 ± 13.8 beats min(-1) during CONT and similar (17.2 ± 7.7 beats min(-1), p = 0.95) during PROP but smaller (p < 0.001) during GLYC and PROP+GLYC (9.8 ± 9.6 and 8.1 ± 7.6 beats min(-1)). Cardiac output was enhanced by hypoxia (p < 0.002) to an extent that was similar between CONT, GLYC, and PROP+GLYC (2.3 ± 1.9, 1.7 ± 1.8, and 2.3 ± 1.2 l min(-1), p > 0.4) but larger during PROP (3.4 ± 1.6 l min(-1), p=0.004). Our results demonstrate that the tachycardic effect of hypoxia during exercise partially relies on vagal withdrawal. Conversely, sympathoexcitation either does not contribute or increases HR through mechanisms other than β-adrenergic transmission. A potential candidate here for is α-adrenergic transmission which could also explain why a tachycardic effect of hypoxia persists during combined β-adrenergic and muscarinic receptor inhibition.