To evaluate the effect of breathing 50 ppm carbon monoxide (CO) on exercise capacity in persons with anemia, 10 nonsmoking subjects with chronic anemia (mean hemoglobin 8.9 g%) were studied. No subject had heart or lung disease. By double-blind, randomized, crossover design, duration of fatigue-limited exercise after breathing CO and purified air for 1 hr was compared. Mean carboxyhemoglobin levels increased from 2.14 to 3.38% after breathing CO and decreased from 2.15 to 1.86% after breathing purified air, P less than 0.004. Mean exercise duration decreased from 270.8 to 221.0 sec after breathing CO in contrast to an increase from 267.9 to 271.6 sec after breathing purified air, P less than 0.0001. Hence, in the absence of clinical heart or lung disease, increasing carboxyhemoglobin concentrations aggravate exercise performance in nonsmokers with chronic anemia.