Recognition and diagnosis of acute human immunodeficiency virus (HIV) infection in the primary care setting presents an opportunity for patient education and health promotion. Symptoms of acute HIV infection are nonspecific (e.g., fever, malaise, myalgias, rash), making misdiagnosis common. Because a wide range of conditions may produce similar symptoms, the diagnosis of acute HIV infection involves a high index of suspicion, a thorough assessment of HIV exposure risk, and appropriate HIV-related laboratory tests. HIV RNA viral load testing is the most useful diagnostic test for acute HIV infection because HIV antibody testing results are generally negative or indeterminate during acute HIV infection. After the diagnosis of acute HIV infection is confirmed, physicians should discuss effective transmission risk reduction strategies with patients. The decision to initiate antiretroviral therapy should be guided by consultation with an HIV specialist.