Aerobic exposure of human hemoglobin in 1:1 molar ratio to sodium nitrite induced an immediate and progressive formation of methemoglobin. Neither lag nor autocatalytic phases were observed, contrary to what was seen when diluted hemoglobin in buffered solutions was used. Hemolyzed whole blood, washed red cells with their plasma replaced by saline, and whole blood were exposed to identical sodium nitrite concentrations. In the presence of oxygen, the speed of methemoglobin formation was three to four times faster in the hemolyzed and plasma-free samples than in whole blood. The maximum rate was reached within the first minute of the reaction. Restoring plasma to washed red cells reduced the rate to that of whole blood; restoring plasma to hemolyzed red cells had no effect on rate. We advance the hypothesis that sodium nitrite or its derivatives form a complex with some element of the blood plasma which slows the passage of nitrite through the red cell membrane without hindering the oxidative capacity of the nitrite. With no free oxygen present, whole blood, washed red cells in saline, and hemolyzed blood all showed a similar rate of methemoglobin formation when exposed to a 1:1 molar ratio of sodium nitrite. The presence of nitrosylhemoglobin formed in the anaerobic reaction seems to be a for the lack of changes seen in the reaction.