We describe two cases of rectal herpes simplex virus (HSV) infection in men that clinically mimicked rectal adenocarcinoma. Herpes infection in this location more commonly presents as an anal mass with viral inclusions in squamous epithelial cells. We report these cases to increase awareness of the unusual presentation as a proximal rectal mass with viral inclusions in endothelial cell nuclei. One patient was HIV-positive, and the other one had a history of having sex with men (MSM). Both patients had a thickened rectal wall with prominent lymphadenopathy on computed tomography (CT) scan, suspecting for malignancy. Biopsy showed abundant granulation tissue, necrosis, and inflammatory infiltrate composed predominantly of lymphocytes with admixed numerous plasma cells, eosinophils, and neutrophils. Rare granulation tissue vessels were lined by endothelial cells with nuclear molding and chromatin margination, and nuclei that were positive for HSV immunohistochemistry (IHC). One patient had confirmatory viral culture from biopsy of the ulcerated rectal mass. Both patients had symptom resolution following treatment for HSV. HSV should be considered in the differential diagnosis of rectal inflammatory masses, particularly in immunocompromised, HIV-positive, and MSM patients.