Infection with the newly discovered human metapneumovirus (hMPV) may lead to hospitalization of children with lower respiratory tract infection (LRTI), although the pathogenesis thereof remains to be elucidated.This hypothesis-generating study involved a cohort of children randomized to receive 9-valent conjugate pneumococcal vaccine or placebo and who were tested for hMPV infection when hospitalized for LRTI. By use of a nested reverse-transcription polymerase chain reaction assay targeted at amplifying a fragment of the hMPV fusion (F) protein gene, 202 such infections were identified among 2715 episodes of LRTI in children.Among human immunodeficiency virus (HIV)-uninfected children who had received 3 doses of conjugate pneumococcal vaccine, the incidence of hMPV-associated LRTI was reduced by 45% (95% confidence interval [CI], 19%-62%; P = .002), and the incidence of clinical pneumonia was reduced by 55% (95% CI, 22%-74%; P = .003). Similarly, in fully vaccinated HIV-infected children, the incidence of hMPV-associated LRTI was reduced by 53% (95% CI, 3%-77%; P = .035), and that of clinical pneumonia was reduced by 65% (95% CI, 19%-85%; P = .020).The pathogenesis of hMPV-associated LRTI that results in hospitalization of both HIV-infected and -uninfected children involves bacterial coinfection with pneumococcus, and a significant proportion of these hospitalizations may be prevented by vaccination with pneumococcal conjugate vaccine.