Langerhans Cell Histiocytosis (LCH) is a rare histiocytic disorder that involves various organ systems. Recognizing gastrointestinal (GI) tract involvement in LCH is crucial, as GI cases, even without high-risk organ involvement, may be refractory to initial as well as second line therapy. Here, we report two cases of LCH with GI involvement, that were refractory to vinblastine, prednisone and cytarabine, and ultimately required clofarabine to reach clinical remission. We propose that clofarabine should be further studied as a first choice for second line treatment for GI-LCH cases and that GI involvement should be considered as high risk in the LCH risk stratification algorithm.