Deep vein thrombosis (DVT) occurs most commonly in the lower extremities and is related to the Virchow triad. While reactivation of the varicella-zoster virus (VZV) is rare when it occurs in the lower extremity dermatome, we present and discuss herpes zoster infection in immunocompromised individuals, which has similar manifestations yet can lead to unexpected, serious, life-threatening DVT complications. A 52-year-old woman with overweight and diabetes mellitus presented to the emergency department with 3 days of fever and a sudden, painful, swollen left leg. There was no history of chickenpox, trauma, surgery, or immobilization. She was using insulin glulisine and glargine. The physical examination was normal, except for a skin eruption characterized by a vesicle-pustule-blister group that followed the L4–L5 dermatome. Laboratory tests revealed leukocytosis and increased D-dimer levels. A duplex ultrasound was performed, which showed a thrombotic filling defect in the left common femoral vein and DVT in the left leg. The patient was treated with oral acyclovir, subcutaneous injection of fondaparinux, insulin glargine, and glulisine. Her symptoms improved within 7 days during her inpatient stay. After discharge, a follow-up duplex ultrasound evaluation revealed a reduced thrombus in the left common femoral vein. This case highlights that VZV reactivation in immunocompromised individuals can be complicated by DVT. It requires heightened clinical awareness of herpes zoster and related complications with similar manifestations, to provide precise and prompt treatment, and prevent worse outcomes. (Iranian Heart Journal 2024; 25(4): 111-116)