Background: Atypical femoral fracture (AFF) is a tensile fracture with unique radiographic and clinical features that differ from ordinary osteoporotic femoral fractures. Denosumab is a novel agent that inhibits osteoclastic activity, reducing bone resorption. Within the past few years, several case reports indicated that patients on denosumab prescription are at risk of AFF. The purpose of this review was to discuss the current evidence regarding this association and draw recommendations for clinicians about the use of denosumab in osteoporotic patients, until such evidence is established in future studies. Methods: A computer search of Medline (through PubMed and OVID search) engines was conducted using the following keywords: "Denosumab" and "atypical femoral fractures". Furthermore, we reviewed the reference list of included studies for further citations. Results: We identified 9 case reports, 5 clinical trials, and 1 prospective observational study that have reported data regarding the incidence of AFF in patients on denosumab prescription. Conclusions: Denosumab is an effective treatment for osteoporosis; however, there is a growing number of reports regarding its association with AFF. Causality needs verification in future observational and interventional studies; meanwhile, screening for AFF in patients receiving denosumab and reevaluating the optimal antiresorptive therapy in osteoporotic patients is recommended.