Six hundred twelve invasive and noninvasive Streptococcus pneumoniae isolates were examined. Serogrouping was performed by the latex agglutination test and serotyping by the quellung reaction. Susceptibilities to macrolides were determined by Etest. The presence of mef(A), mef(E), and erm(B) genes were detected by polymerase chain reaction. Outpatient macrolide and lincosamide consumption was expressed in defined daily doses per 1000 inhabitants daily (DID). A significant increase in macrolide resistance rate was noted from 7.4% (14/190) in the period 1985 to 1996 to 53.7% (144/268) in 2001 to 2004 (P = 0.003). An increase in macrolide and lincosamide consumption was also observed from 4.31 +/- 0.72 in 1990 to 1996 to 6.97 +/- 1.02 DID in 2001 to 2004 (P = 0.002). Macrolide resistance was mediated by mef(E) gene in 44.5% of isolates, mef(A) in 25.6%, erm(B) in 19.8%, both erm(B) and mef(E) genes in 4.8%, and none of the examined genes in 5.3%. In the setting of increasing macrolide use, there has been a parallel increase in macrolide resistance among pneumococci in our region. The predominant resistance determinants were the mef(A) and mef(E) genes.