HIV infection may mimic a variety of other medical illnesses. Specific differential diagnosis depends on the mode of presentation. In patients presenting with constitutional symptoms such as weight loss and fevers, differential considerations include cancer, chronic infections such as tuberculosis and endocarditis, and endocrinologic diseases such as hyperthyroidism. When pulmonary processes dominate the presentation, acute and chronic lung infections must be considered as well as other causes of diffuse interstitial pulmonary infiltrates, including SARS-CoV-2 infection (COVID-19). When neurologic disease is the mode of presentation, conditions that cause mental status changes or neuropathy—eg, alcohol use disorder (alcoholism), liver disease, kidney dysfunction, thyroid disease, and vitamin deficiency—should be considered. If a patient presents with headache and a cerebrospinal fluid pleocytosis, other causes of chronic meningitis enter the differential. When diarrhea is a prominent complaint, infectious enterocolitis, antibiotic-associated colitis, inflammatory bowel disease, and malabsorptive syndromes must be considered.