The simultaneous changes in serum prealbumin, orosomucoid (alpha-acidglycoprotein, AGP), and C-reactive protein (CRP) were evaluated in 36 newborn infants with septicemia (n = 20), meningitis (n = 10), arthritis (n = 5), and peritonitis (n = 1). In 29 patients with a favorable outcome the values for serum prealbumin and CRP showed a rapid return toward normal: in 2 to 3 days serum prealbumin increased by 84% from the basal value and remained at (mean +/- 1 SD) 0.11 +/- 0.02 gm/L. Serum CRP decreased from 85 +/- 75 mg/L (range 0.15 to 206 mg/L) to 49 +/- 64 mg/L (2 to 210 mg/L) at 3 to 4 days of evolution and to normal values at day 13 to 16. The changes in serum orosomucoid values were slower, from 1.33 +/- 0.75 gm/L to 1.16 +/- 0.75 gm/L at day 13 to 16, with normalization after 20 to 30 days. Serum orosomucoid values returned to the normal range with the clinical improvement. In some patients the orosomucoid/prealbumin ratio decreased earlier than the serum orosomucoid concentration. Seven patients died, and in four of these in whom at least three values could be determined serum CRP and orosomucoid remained very high, whereas serum prealbumin did not increase or subsequently decreased. These data show an inverse change in serum CRP and prealbumin concentrations in infected neonates. The immediate decrease in CRP reflects the effect of treatment, whereas the later decrease in serum AGP parallels the clinical course of the infection. Thus the determination of these proteins can help to guide the treatment of infection in newborn infants.