To investigate the reasons of growing resistance problem of Streptococcus pneumoniae against macrolide in Chongqing, a retrospective method was employed to measure the minimal inhibition concentrations (MIC) of macrolide antibiotic against 1,210 S. pneumoniae clinic isolates. The defined daily doses (DDDs) of macrolide antibiotic were calculated. Polymerase chain reaction (PCR) was used to determine the presence of the erythromycin-resistant genes in 100 macrolide-resistant S. pneumoniae isolates. A decrease in macrolide consumption, from 371,100 DDDs in 2002 to 182,500 DDDs in 2005 (51% reduction); however, the rate of erythromycin resistance in S. pneumoniae showed continued increase from 88.0% in 2002 to 96.0% in 2005. No linear correlation was observed between the decline in macrolide consumption and continued increase in resistant rate in S. pneumoniae. In 100 macrolide-resistant S. pneumoniae isolates, 68 had both erm(B) and mef(A) genotypes, 10 only had the erm(B), 20 only had the mef(A). Co-existences of ribosomal modification coded by erm(B) gene and efflux effects coded by mef(A) gene were the main resistance mechanism against macrolides and might be attributed to the high drug resistance of S. pneumoniae in Chongqing. Pediatr Pulmonol. 2009; 44:917-921. (C) 2009 Wiley-Liss, Inc.