Metabolic acidosis has previously been described in the gray baby syndrome, but has not been documented as a presenting feature. Four seriously ill children (bronchiolitis, hypoaldosteronism, dysautonomia, Reye syndrome), ages 4 months to 11 years, received chloramphenicol (CAP) intravenously. After initial stabilization, unexplained metabolic acidosis occurred 40 to 81 hours after beginning CAP. Serum CAP concentrations were 84, 62, 80, and 30 micrograms/ml, respectively, when acidosis was recognized. Hypotension, hypothermia, and abdominal distension occurred a mean of 23 hours after the onset of acidosis. Acidosis resolved and signs of the gray baby syndrome cleared with the decrease in serum CAP concentrations. Metabolic acidosis should be considered an early sign of CAP toxicity, and CAP should be used in reduced doses in severely ill patients, especially those with liver dysfunction.