Despite decades of research, the magnitude and time course of hematologic and plasma volume (PV) changes following rapid ascent and acclimation to various altitudes are not precisely described. To develop a quantitative model, we utilized a comprehensive database and general linear mixed models to analyze 1,055 hemoglobin ([Hb]) and hematocrit (Hct) measurements collected at sea level and repeated time points at various altitudes in 393 unacclimatized men ( n = 270) and women ( n = 123) who spent between 2 h and 7 days at 2,500–4,500 m under well-controlled and standardized experimental conditions. The PV change (ΔPV) was calculated from [Hb] and Hct measurements during a time period when erythrocyte volume is stable. The results are 1) ΔPV decreases rapidly (~6%) after the 1st day at 2,500 m and [Hb] and Hct values increase by 0.5 g/dl and 1.5 points, respectively; 2) ΔPV decreases an additional 1%, and [Hb] and Hct increase an additional 0.1 g/dl and 0.2 points every 500-m increase in elevation above 2,500 m after the 1st day; 3) ΔPV continues to decrease over time at altitude, but the magnitude of this decrease and subsequent increase in [Hb] and Hct levels is dependent on elevation and sex; and 4) individuals with high initial levels of [Hb] and Hct and older individuals hemoconcentrate less at higher elevations. This study provides the first quantitative delineation of ΔPV and hematological responses during the first week of exposure over a wide range of altitudes and demonstrates that absolute altitude and time at altitude, as well as initial hematologic status, sex, and age impact the response.