Besides the well-known systemic immune deficiency, also a regional immune deficiency, labeled as ”immunocompromised district“ (ICD), has been documented and focused in the recent years. The objective of the study is to gain more insights into the mechanisms involved in systemic and local immune destabilization. A 35-year-old, homosexual, and drug-addicted HIV+ man presented with a single nodule of Kaposi sarcoma (KS) located on the penis, where a slow to heal herpes zoster had appeared 2 months before. It has been assumed that the unusual penile location of herpes zoster facilitated the outbreak of KS in the affected dermatome because of a viral damage to sensory nerve fibers of the same dermatome. This damage, by interfering with the immunoregulatory function of neuropeptides released by nerve endings in that area, may have caused a regional alteration of the immune control favoring the local onset of the ”opportunistic“ angiogenic tumor (KS). In a few words, an ICD took place in an immunocompromised patient, thus introducing a more vulnerable site in an already vulnerable subject. The present case is the second one in the literature to document an ICD in the setting of preexisting systemic immune deficiency.