The geometric mean of plasma hemoglobin concentrations assayed by a modified benzidine procedure in 14 patients with sickle cell anemia (S-S hemoglobin) during 18 painful crises was 8.5 mg. per 100 ml. as compared with 5.9 mg. per 100 ml. during quiescent periods and 0.3 mg. per 100 ml. in normal controls. On the first and second days of crisis, plasma hemoglobin values were highest (15.3 and 10.1 mg. per 100 ml., respectively), dropping precipitously to steady state plateaus, sometimes with secondary rises and usually paralleling clinical symptomatology. Methemalbumin, free hemoglobin, and haptoglobin-bound hemoglobin were estimated by plasma electrophoresis and scan of benzidine-stained paper strips. Fraction values during crisis were variable, with high initial methemalbumin or free hemoglobin, or both, and often elevations of haptoglobin-bound hemoglobin. The highest plasma hemoglobin observed, 40.8 mg. per 100 ml., could be accounted for by intravascular hemolysis of only 20 ml. of blood. This indicates that “hyperhemolysis” in sickle cell crisis is minor, presumably secondary, and different in principle from the massive intravascular hemolysis observed in immunohemolytic anemias, hereditary enzyme deficiencies, or hemolytic septicemias.