Analysis of penicillin-nonsusceptible Streptococcus pneumoniae (PNSP) isolates in Hong Kong by use of a combination of antibiogram typing, serotyping, multilocus sequence typing, and pulsed-field gel electrophoresis indicated that the dissemination of PNSP was the result of the spread of international clones: variants of the Spain(23F)-1 or Spain(6B)-2 clones were the predominant PNSP isolates from 1994 to 1997 and remained so, but Taiwan(19F)-14 and Taiwan serotype 6B clones were disseminated in Hong Kong in 1999 and 2000. Concomitant changes in antibiotic susceptibility profiles, with the rate of susceptibility to chloramphenicol rising from 10% in the period from 1994 to 1997 to 31% (P < 0.001) in 1999 and 2000, were noted to accompany the shift of clones.