Monkeypox is the latest reemerging zoonosis worldwide. Anyone is susceptible to contracting this infection; however, the clinical presentation may be atypical in a particularly vulnerable group that identifies as men who have sex with men. Herein, we present two cases of patients diagnosed with monkeypox infection, both of whom were also co-infected with human immunodeficiency virus (HIV) and exhibited different degrees of immunosuppression. Notably, the clinical presentations differed significantly. Patients co-infected with HIV are prone to develop clinical features ranging from barely visible lesions to severe or even fatal disease.