OBJECTIVE: To determine whether reported increases in Streptococcus pneumoniae resistance, as determined by in vitro antimicrobial susceptibility testing, correlate with the clinical efficacy of clarithromycin in treating patients with acute exacerbations of chronic bronchitis (AECB) or community-acquired pneumonia (CAP). BACKGROUND: Surveillance data on antimicrobial resistance suggest that the overall rate of S. pneumoniae resistance in vitro in the United States has increased to approximately 45% during the past decade. S. pneumoniae is showing increased resistance to penicillin, other beta-lactams, and macrolides. Despite this increased resistance, the clinical efficacy of clarithromycin does not appear to be diminished to the degree suggested by reported resistance rates. The author examined several studies of clarithromycin in patients with AECB or CAP that demonstrate S. pneumoniae eradication rates in vivo of approximately 92%. The discordance between reported increases in resistance of S. pneumoniae isolates in vitro and the eradication rate with clarithromycin in vivo is discussed in light of 5 observations. RESULTS: First, surveillance data on S. pneumoniae resistance rates to clarithromycin may be overestimated. Second, efflux mutant strains may not be clinically resistant. Third, host immune defenses play a role in treatment outcomes. Fourth, in vitro resistance may not correlate with in vivo clinical success. Finally, clarithromycin and its active metabolite, 14-OH-clarithromycin, attain high concentrations in patients. CONCLUSION: Reported increases in the prevalence of S. pneumoniae resistance do not appear to have had proportional effects on the clinical efficacy of clarithromycin in the treatment of patients with AECB or CAP caused by S. pneumoniae.