The plasma protein binding of sufentanil has been studied in newborns, infants (0.5 ± 0.3 yr), children (6.8 ± 3.0 yr), and adults (39.5 ± 9.0 yr). Binding of sufentanil was determinedin vitroby equilibrium dialysis, and radioactive tritiated sufentanil was used for the determination of drug concentrations in plasma and buffer. The free fraction of sufentanil was significantly higher in the newborn (19.5 ± 2.7%;P< 0.01) than in the other age groups. The free fraction was also significantly higher in infants (11.5 ± 3.2%;P< 0.01) than in children (8.1 ± 1.4%) or in adults (7.8 ± 1.5%) but did not differ significantly between children and adults. The free fraction of sufentanil was strongly correlated with the α1-acid glycoprotein plasma concentration (r = −0.73;P< 0.001) whereas it was weakly correlated with albumin plasma concentration (r = −0.35;P< 0.05). These data suggest that the lower concentration of α1-acid glycoprotein in newborns and infants probably accounts for the decrease in protein binding of sufentanil in these age groups when compared with that in older children or adults. The increased free fraction in the neonate might contribute to the enhanced effects of lipophilic opioids in the neonate.