The purpose of this study was to determine if chronic exposure to low levels of carbon monoxide (CO) in man results in tissue hypoxia. For this reason, nine smokers (more than one pack of cigarettes per day) were studied. The presence of hypoxia was assessed by measurement of red cell mass (RCM). The effect of CO on intraerythrocytic factors involved with oxygen delivery was determined by measurement of oxygen-hemoglobin affinity (P50) and of red cell 2,3-diphosphoglycerate (DPG) and adenosine triphosphate (ATP). Values were compared to those of 18 nonsmokers of similar age, sex, and race. Values for carboxyhemoglobin (COHb), RCM, hemoglobin, hematocrit, and red cell count were significantly higher in the smokers. DPG levels were unaltered, while P50 and ATP levels were significantly lower in smokers. These data suggest that chronic exposure to low levels of CO results in tissue hypoxia, probably as a result of decreased blood oxygen carrying capacity and increased blood-O2 affinity. Adaption is reflected in an increased RCM and not by intraerythrocytic changes. The response in RCM may be to levels seen in polycythemia vera, as evidenced by a value of 37.6 in one smoker whose RCM fell to normal after discontinuing cigarettes. This study indicates that smoking causes mild erythrocytosis comparable to that seen in spurious or stress polycythemia. It also suggests that chronic exposure to low levels of CO may further embarrass tissue oxygen supply in patients with anemia, heart disease, chronic lung disease, and cerebral vascular disease in whom oxygen delivery to tissues is already marginal.