Our case series report is the first documented depiction of the appearance of aphthous ulcers secondary to imiquimod application. This case series presentation discusses the underlying pathophysiology of aphthous ulcer development and imiquimod therapy in terms of the stimulation of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-alpha), The literature review Suggests more than just a mere coincidence for the development of aphthous ulcers subsequent to the treatment of actinic cheilitis with imiquimod application.