CMV colitis is usually considered a complication of immunosuppression or steroid-refractory ulcerative colitis (UC). We report three adults with severe colitis evaluated with serum CMV PCR and targeted biopsies/CMV immunohistochemistry. Case 1: immunocompetent man with first-episode Mayo 3 left-sided colitis after viral prodrome; PCR strongly positive; rapid response to IV ganciclovir. Case 2: UC ~1 year after stopping biologics, post–C. difficile; Mayo 3 pancolitis with deep ulcers; PCR+ and biopsy inclusions; improved with ganciclovir plus UC therapy with PCR clearance. C3: extensive UC relapsing during high-dose steroids and infliximab induction; CMV IHC+ and PCR+; marked improvement after ganciclovir. We propose early CMV testing in severe/atypical flares, post-infectious triggers, or relapse despite steroids/biologics to guide timely antivirals and reduce recurrent steroid exposure.