Cronkhite-Canada syndrome (CCS) is a rare, nonfamilial syndrome that occurs in the sixth to seventh decades of life. It is characterized by acquired gastrointestinal polyposis with an associated ectodermal triad, including alopecia, onchodystrophy, and hyperpigmentation. CCS is characteristically a progressive disease, with a high mortality rate despite medical interventions. Disease complications are typically secondary to severe malnutrition, malignancy, GI bleeding, and infection. CCS is believed secondary to immune dysregulation; however, the underlying etiology remains to be determined. Treatment for CCS is largely anecdotal, and randomized controlled therapeutic trials are lacking due to the rarity of the disease. Aggressive nutritional support in conjunction with immunosuppression has been used previously with inconsistent results. In this report, we describe the presentation and diagnosis of a case of CCS and report encouraging treatment response with anti-TNF therapy.