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Background: Pityriasis rosea is a self-limiting, acute, or subacute inflammatory skin disease that usually starts with a herald patch on the trunk and progresses to a generalized rash over the trunk and limbs. Some clinical trials have suggested that antibiotic macrolides help shorten the duration of skin manifestations in pityriasis rosea; however, the extent of the benefits is unclear. Objective: To evaluate the effectiveness of antibiotic macrolides compared to placebo in pityriasis rosea. Methods: A computerized search was performed using different databases, including Cochrane, Embase, and PubMed. Five randomized controlled trials were included. Then, statistical analyses of the outcome data extracted from the studies were performed using Rex Software (version 3.0.1). Results: Total 160 records were identified by searching databases including Cochrane, Embase, and PubMed. The results of the meta-analysis demonstrated statistical differences between the use of antibiotic macrolides and placebo in the complete and partial resolution of pityriasis rosea (effectiveness) (RR: 1.84, 95% CI: 1.21∼2.78, p=0.004). However, in subgroup analyses, there were no statistical differences compared to placebo in the skin manifestation effectiveness group for azithromycin and clarithromycin, whereas erythromycin showed statistical differences. Conclusion: Erythromycin was superior to placebo in the treatment of pityriasis rosea. However, this study had some limitations, including insufficient articles and data. Therefore, further investigation is required.