The objective of this study was to evaluate the comparative efficacy of tulathromycin at resolving bovine respiratory disease in North American feedlot cattle. This study was a systematic review of published literature. A search was conducted to identify all manuscripts relating to antibiotic treatment of cattle with respiratory disease. Relevant studies reported treatment with tulathromycin of naturally occurring respiratory disease in beef cattle in North America. Studies which failed to use randomization to minimize bias were excluded from the review. The relative risk of retreatment for bovine respiratory disease was calculated for each study included in the final review. Initially, 782 potential manuscripts were identified. After relevance screening and quality assessment, 21 high quality manuscripts were available for analysis. Two peer reviewed publications and two technical reports describing 14 trials compared tulathramycin with tilmicosin or florfenicol. In the meta-analysis of studies comparing tilmicosin with tulathromycin, the summary Mantel–Haenszel relative risk was 0.51 (95% confidence interval 0.45–0.57). It was not possible to calculate a summary Mantel–Haenszel relative risk comparing florfenicol with tulathromycin as the only three studies reported this comparison. When using a meta-analysis to combined data from randomized clinical trials reporting treatment with tulathromycin or either florfenicol or tilmicosin, tulathromycin was associated with an approximately 50% reduction in the risk of re-treatment for bovine respiratory disease compared with treatment with tilmicosin.