We studied the major determinants of opsonophagocytosis against Streptococcus pneumoniae serotypes 14 and 19 in paired cord/maternal sera from 27 healthy term and 24 preterm infants in an attempt to gain more insight in the susceptibility of newborns to pneumococcal infection. For both pneumococcal serotypes studied, opsonic activity in neonatal sera varied greatly, but was moderately to profoundly deficient when compared to paired maternal sera, both in preterm (34.5 and 34.9% of the activity in maternal serum, for serotypes 14 and 19, respectively, p<0.001 for both) and in term serum (43.5 and 52.7% of the activity in maternal serum, for serotypes 14 and 19, respectively, p<0.001 for both). The opsonic deficiency in preterm sera could be ascribed to a diminished level of the major opsonins for pneumococci, i.e. complement factor C3 deposited on the bacterial surface (69.5 and 66.2% of C3 deposition in maternal serum on serotypes 14 and 19, respectively, p<0.01 for both) and specific anticapsular IgG antibodies (48.5 and 14.1% of maternal levels for serotypes 14 and 19, respectively, p<0.001 for both). However, the opsonic defect in serum from term infants could not be explained in a similar way, because C3 deposition and specific anticapsular IgG levels were equal to the values found in the paired maternal sera. Therefore, we conclude that the opsonic defect in newborn serum for pneumococci cannot be solely explained by a deficiency in the major opsonins for these bacteria. A dysfunction in these opsonins seems to be a more likely explanation for the observed opsonic defect in the neonate.