Background: Antimicrobial resistance of Streptococcus pneumoniae (S. pneumoniae) has shown major changes in recent years. On the other hand, macrolide antibiotics are being increasingly used in clinical practice. Several studies have reported increased resistance to this group of antibiotics, while there is no comprehensive information in this area. Accordingly, the present study was designed to estimate the resistance of S. pneumoniae to macrolides in Iran. Materials and Methods: In this review, articles (2000-2017), evaluating the level and type of S. pneumoniae resistance to macrolides in Iran, were extracted by searching different databases, and the results were analyzed. Results: A total of 25 relevant articles were retrieved and analyzed. Overall, 2723 cases had been recruited in these studies. The mean percentage of resistance to macrolides was estimated at 48. 43% (CI, 38. 8-57. 9%). In the majority of reported cases, the resistance mechanisms included ribosomal methylation (i. e., ermB mutation), dual resistance, and efflux-mediated resistance. Conclusion: Based on the findings, the resistance rates are considerable in different cities of Iran. Therefore, without determining the type of drug resistance in clinical samples, use of macrolides is not recommended for treatment purposes. In addition, considering the type of resistance mechanisms in Iran, use of higher drug doses is probably ineffective.