Introduction: Multifocal osteosarcoma (MFOS) is an aggressive presentation of osteosarcoma characterized by multiple skeletal lesions without visceral metastasis. Despite decades of clinical recognition, its biological basis, classification, and optimal management remain poorly defined, particularly regarding distinctions between synchronous and metachronous disease.

Hypothesis: Synchronous and metachronous MFOS differ in pathogenesis, imaging characteristics, clinical behavior, treatment feasibility, and prognosis.

Methods: A narrative review of the literature was conducted using PubMed, Scopus, and Google Scholar. Studies addressing the definition, classification systems, pathogenesis, imaging characteristics, treatment approaches, and outcomes of MFOS were identified and synthesized, with particular emphasis on differences between synchronous and metachronous forms.

Results: MFOS accounts for approximately 1.5% of osteosarcoma cases. Synchronous MFOS typically presents with widespread sclerotic lesions, limited surgical options, and poor survival. In contrast, metachronous MFOS more closely resembles conventional osteosarcoma, is more often amenable to surgical resection, and demonstrates comparatively improved outcomes. Genetic predisposition syndromes and microenvironmental factors appear to play contributory roles in selected cases. However, no definitive molecular markers currently exist to distinguish true multicentric disease from early skeletal metastasis.

Conclusion: MFOS remains a diagnostically and therapeutically challenging condition with distinct clinical and prognostic differences between synchronous and metachronous forms. Improved molecular characterization and collaborative research efforts are needed to refine classification, guide treatment strategies, and improve outcomes in this rare and aggressive disease.