Chronic herpes infections in immunocompromised patients exhibit uncommon features both on clinical and histopathologic levels, which can make correct diagnosis challenging. Better defining histopathologic criteria to identify chronic herpes infection in immunocompromised patients would be of great diagnostic value. In a single-center study, clinical and pathological data of herpes infections confirmed by biopsy was collected. We identified 42 cases overall, of which 21 were from immunocompromised patients and performed a detailed histopathologic pattern analysis of all lesions. In immunocompromised patients, vasculitis was seen in 2/21 cases (9.5%). Involvement of the sweat duct epithelium and/or sebaceous glands was observed in none of the HIV-infected patients but in 5/11 (45.4%) transplant patients with herpes infection. This feature was solely found in patients with acute herpetic lesions (5/5). In the process of histopathologic review, we identified a previously unrecognized morphological pattern of herpes simplex virus infection in immunocompromised patients. The individual clinical history and morphological pattern identified is described for multiple affected patients. In summary, in immunocompromised patients, histopathologic diagnosis of herpes infection can be challenging, in particular in chronic lesions, which lack the presentation of typical herpetic keratinocytes. In our study, we identify angioplasmacellular hyperplasia as a new histopathologic clue, which may be helpful in recognizing chronic herpes infection in immunocompromised patients. Further studies are warranted to implement this clue into routine diagnostics.