A 38 year old Caucasian male diagnosed with severe ileo-colonic Crohn's disease (complicated with an ileo-cecal valve stricture) 20 years ago presented with abdominal pain, diarrhea and weight loss for 3 months. Mesalamine therapy at initial diagnosis and a subsequent trial of infliximab, adalimumab and natalizumab failed to induce remission. A disease flare persisted with endoscopic evidence of moderate to severe inflammation along the terminal ileum(TI) and entire colon(edema, erythema, friability, granularity,ulcerations and pseudopolyps). Remission was achieved with Vedolizumab and oral prednisone 40mg with a successful taper down to only 25mg daily due to symptoms recurrence. He reported less frequent, less bloody and more formed stools on the regimen. Pertinent medical history includes Clostridium difficile infection(CDI) 2 months after starting vedolizumab that failed oral vancomycin therapy but resolved with fidaxomycin. A surveillance colonoscopy a year after intiating vedolizumab revealed similar findings as mentioned above with significant improvement in endosocopic appearance (pseudopolyps, scarring surrounded by normal mucosa) and microscopic inflammation (architectural distortion, inflammatory cells in lamina propria). Additionally,3 new multi-lobulated cecal polyps too large to be removed endoscopically were biopsied as dysplasia was of concern. Pathology confirmed Histoplasma and he began therapy with Itraconazole for primary gastrointestinal Histoplasmosis(GIH) in the absence of systemic infection with reported improvement in symptoms on reevaluation at 3 months.His diarrhea is at his baseline of 6 bowel movements a day, without rectal bleeding, abdominal pain or weight loss. He is pending a colonoscopy in 1 month. Histoplasmosis is common among patients taking TNF-α inhibitors with related hospitalizations increasing by 15% per year in the last decade and a mortality rate reported at 20%. While there is evidence that vedolizumab increases risk of CDI and cytomegalovirus colitis, data on risk of fungal infections is lacking. GIH frequently involves the TI and cecum secondary to systemic disease making this case of primary GIH intriguing. Further, presentation as a colonic mass is rare, with 20 cases reported thus far. Treatment involves systemic antifungals. Providers should be vigilant for fungal infections among patients on biologics and take timely steps to diagnose and treat them to reduce resultant morbidity and mortality.Figure 1Figure 2Figure 3