Background: Pityriasis Rosea (PR) is an acute inflammatory and self-limiting skin disorder, sometimes with troublesome symptoms. To date, there are few treatments available for this disorder. Aim: Compare the traditional treatment with erythromycin to a newly introduced antiviral treatment acyclovir for PR. Materials and Methods: Patients with clinically confirmed diagnosis of PR, matching our exclusion criteria, were enrolled. They were randomized in two groups that received high-dose oral acyclovir or erythromycin. The participants were evaluated two, four, and eight weeks after commencement of the study and followed for one year. Results: A total of 30 patients including 15 males and 15 females completed the study. After eight weeks, 13 patients in the acyclovir group experienced complete response, while in the erythromycin group only six patients had complete response (P < 0.05). Also, patients in the acyclovir group experienced faster resolution of pruritus in comparison with the erythromycin group (not significant). No adverse drug reaction was detected in both groups. Conclusion: It seemed that a high-dose of oral acyclovir was a safe and effective therapy for PR, although this remained to be confirmed in larger studies.