Objective: To assess the cost-effectiveness of empirical outpatient treatment options in Canada for community-acquired pneumonia (CAP) in the presence of antimicrobial resistance. Methods: A multi-country decision analytic model to assess the clinical and economic consequences of antimicrobial resistance, developed for mild-to-moderate empirical CAP outpatient treatment, was adapted to Canada. Treatment algorithms involved first- and second-line treatment in the community, and incorporated follow-up after treatment failure due to resistance or other reasons and resulting hospitalizations. Comparators included (1) first-line treatment with azithromycin, a generic macrolide prescribed in Canada, followed by moxifloxacin, a fluoroquinolone, and (2) first-line treatment with moxifloxacin followed by azithromycin upon failure. Clinical failure rates with antimicrobial-susceptible and -resistant pathogens were obtained from the literature or estimated. Resistance and co-resistance prevalence to first- and second-line therapy for the major CAP pathogens were also derived from local surveillance studies. Resource use was obtained from Canadian published sources. Total costs were estimated using standard Ontario sources and a third-party payer perspective. Outcome measures included first-line clinical failure, second-line treatment and hospitalizations avoided. Results: The base case incremental cost-effectiveness ratios (ICERs) comparing moxifloxacin/azithromycin with azithromycin/moxifloxacin were CDN$96.04 per clinical failure avoided, CDN$118.71 per second-line treatment avoided, and CDN$502.47 per hospitalization avoided. One-way sensitivity analyses demonstrated that the model is robust to change. The probabilistic sensitivity analysis reported a mean ICER of CDN$133 (Sd601.47) per clinical failure avoided and a 22% probability of a moxifloxacin/azithromycin strategy being cost-saving compared to azithromycin/moxifloxacin. Conclusion: Antimicrobial failure significantly affected outcomes and costs in empirical outpatient CAP treatment. Despite the higher costs of proprietary antimicrobial treatments in Canada compared to generic treatments, first-line treatment with a fluoroquinolone effective against the major CAP pathogens, including strains resistant to other antimicrobials, produces significantly better clinical outcomes and relatively low total treatment costs compared to generic drugs.