The treatment of severe flares of ulcerative colitis is based on systemic corticosteroids, immunomodulators such as cyclosporine and azathioprine and in some cases TNF-alpha-antagonists, respectively. These immunosuppressed patients are susceptible for infectious pathogens. Here we report the case of a patient with a severe flare of ulcerative colitis that was first treated with systemic corticosteroids combined with immunomodulators and subsequent with infliximab. The patient then experienced an infection with Clostridium difficile and cytomegalovirus of the colon and a Herpes simplex esophagitis, respectively. After specific treatment the patient responded well to the immunosuppressive therapy. This case illustrates that infections have to be considered before systemic treatment of an acute flare of ulcerative colitis is instituted especially in the case of disease activation during immunosuppressive treatment.