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Although free-floating thrombus (FFT) poses a significant risk of stroke or transient ischemic attack (TIA), optimal management strategies are uncertain. To determine the state-of-the-art of medical interventions for FFT, we conducted a systematic review of the efficacy of various medical interventions and factors influencing FFT resolution and recurrence. A comprehensive search of Embase, PubMed, and ScienceDirect identified 61 studies encompassing 179 patients with FFT-related stroke or TIA treated with anticoagulants, antiplatelets, or their combinations. Primary outcomes assessed were stroke recurrence and thrombus resolution. Statistical analyses (Fisher's exact test, chi-square test, Mann–Whitney test, and Kruskal–Wallis test) utilized significance set at p < 0.05. Over a median follow-up of 7 months, thrombus resolution occurred in 65% of patients, while 11.2% experienced recurrence, primarily as TIAs. Cardioembolism was significantly less common in resolved cases (p = 0.025). Combination therapy (antiplatelets, anticoagulants, and statins) significantly enhanced clot resolution (OR 11.4; 95% CI 1.436–91.91; p = 0.021) compared to monotherapies. Ulcerated plaque was a significant predictor of recurrence (OR 8.2; 95% CI 1.02–66.07; p = 0.048). These findings underscore the superiority of combination therapy in FFT management and highlight the need for targeted interventions in patients with ulcerated plaques to mitigate recurrence risk. [ABSTRACT FROM AUTHOR]