This article presents an unusual case of major recurrent aphthous stomatitis that was refractory to multiple topical and systemic immunosuppressive therapies. Ultimately, thalidomide was selected despite its well-recognized adverse potential, and was successful in producing remission of ulcers. Strict clinical protocols were followed for this therapy in collaboration with numerous medical providers. This case illustrates the ability of multiple oral health and medical providers to collaborate in the diagnosis, management, and follow-up of a patient with an oral vesiculoerosive disease.