Introduction: Pityriasis rosea and secondary syphilis can appear clinically similar but have different causes. An accurate diagnosis, supported by clinical evaluation and testing, is key to differentiating and properly treating them. Objective: To perform a comparative analysis between secondary syphilis and pityriasis rosea. Methodology: Twenty-four articles were reviewed, of which sixteen relevant references were selected after applying inclusion criteria. The sources used were Cochrane, PubMed, and Google Scholar, with search terms in multiple languages. The final bibliography addressed key aspects of secondary syphilis and pityriasis rosea, including a comparative analysis between the two diseases. Results: Despite clinical similarities, careful examination and serological testing allow differentiation of pityriasis rosea from secondary syphilis, preventing diagnostic errors and improving clinical management. Conclusions: Pityriasis rosea and secondary syphilis may appear similar, but an accurate diagnosis requires careful clinical evaluation and serological testing. Identifying their differences is crucial for proper management.