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Background Botulinum toxin (BT), a potent neurotoxin, has been used in clinical medicine since the 1970s for cosmetic and therapeutic purposes. Studies have consistently shown positive outcomes with a very limited adverse effect profile and a conventional understanding that results dissipate after 3 to 5 months. However, more recent evidence suggests that changes in muscle composition, function, and appearance persist for much longer, even years. To examine the potential implications of these findings on cosmetic use of BT injections in reduction of skin lines and wrinkles, we first needed to further our understanding of the current literature on long-term outcomes after repeated BT injections. Methods A comprehensive review of the literature on long-term outcomes after repeated BT injections for cosmetic indications was performed. We evaluated the study designs, and results were compared. Results A total of 22 publications met our inclusion criteria, of which 14 were clinical trials. Few studies extended outcome measurement past 6 months postinjection, and many were funded or supported by industry. However, the studies that extended follow-up saw persistent changes after BT injection, in some cases as far as 4 years postinjection. Conclusion The current body of knowledge on the long-term results after repeated cosmetic BT injections is very limited, and the available literature provides insufficient evidence on how prolonged effects could alter clinical use of BT. Further clinical studies with extended follow-up periods with inclusion of both subjective and objective measured outcomes of appearance and muscle function are required to better understand the long-term impacts of repeated BT injections.