Purpose <p>Platelet-rich plasma (PRP) is a promising orthobiologic therapy for musculoskeletal pathologies. However, its clinical application is influenced by varying legal and regulatory frameworks across regions. This narrative review aims to discuss the regulatory and legal framework for PRP therapy in musculoskeletal pathologies in South America.</p> Methods <p>The authors searched and reviewed contemporary literature on laws and regulations governing platelet-rich plasma use for musculoskeletal pathologies in South America in electronic databases, summarising the findings in a narrative review.</p> Results <p>PRP regulation in South America falls into three categories: (1) countries with clear regulatory frameworks (Argentina, Bolivia, Colombia, Peru), where PRP is legally recognised and governed by specific provisions; (2) countries with emerging or developing regulations (Chile, Ecuador, Paraguay, Suriname, Uruguay, Venezuela, Guyana), where PRP is indirectly regulated under broader blood or tissue laws; and (3) countries permitting PRP only for experimental or research purposes (Brazil). Despite regional efforts to align with international standards, significant disparities exist in legal clarity, safety protocols, and clinical guidelines. These inconsistencies pose risks such as unregulated medical tourism and hinder scientific progress.</p> Conclusion <p>PRP in South America presents three distinct regulatory scenarios: clear, established regulations; emerging or developing frameworks; and use restricted to experimental or research contexts. While most countries align with international safety standards, significant variation persists in how orthobiologics are clinically governed. The future challenge is to unify these regulations and build an international consensus on processing standards that guarantee patient safety and quality, while enabling innovation and legal clarity for clinicians.</p>