To determine if residence at moderate (~2000 m) compared to low (<50 m) altitude reduces acute mountain sickness (AMS) in men during subsequent rapid ascent to a higher altitude. Nine moderate-altitude residents (MAR) and 18 sea-level residents (SLR) completed the Environmental Symptoms Questionnaire (ESQ) at their respective baseline residence and again at 12, 24, 48, and 72 h at 4300 m to assess the severity and prevalence of AMS. AMS cerebral factor score (AMS-C) was calculated from the ESQ at each time point. AMS was judged to be present if AMS-C was ≥0.7. Resting end-tidal CO2 (PETco2) and arterial oxygen saturation (Sao2) were assessed prior to and at 24, 48, and 72 h at 4300 m. Resting venous blood samples were collected prior to and at 72 h at 4300 m to estimate plasma volume (PV) changes. MAR compared to SLR: 1) AMS severity at 4300 was lower (p<0.05) at 12 h (0.50±0.69 vs. 1.48±1.28), 24 h (0.15±0.19 vs. 1.39±1.19), 48 h (0.10±0.18 vs. 1.37±1.49) and 72 h (0.08±0.12 vs. 0.69±0.70); 2) AMS prevalence at 4300 was lower (p<0.05) at 12 h (22% vs. 72%), 24 h (0% vs. 56%), 48 h (0% vs. 56%), and 72 h (0% vs. 45%); 3) resting Sao2 (%) was lower (p<0.05) at baseline (95±1 vs. 99±1) but higher (p<0.05) at 4300 at 24 h (86±2 vs. 81±5), 48 h (88±3 vs. 83±6), and 72 h (88±2 vs. 83±5); and 4) PV (%) did not differ at 72 h at 4300 m in the MAR (4.5±6.7) but was reduced for the SLR (-8.1±10.4). These results suggest that ventilatory and hematological acclimatization acquired while living at moderate altitude, as indicated by a higher resting Sao2 and no reduction in PV during exposure to a higher altitude, is associated with greatly reduced AMS after rapid ascent to high altitude.