CD4 testing is routinely performed when people with human immunodeficiency virus (HIV) (PWH) are hospitalized; however, it is often unhelpful and can even be harmful. Acute stress from sepsis, surgery, cancer, hemorrhage, and viral infections, as well as the effects of medications can temporarily suppress absolute lymphocyte counts (and thus CD4 counts). Most PWH, including most PWH who are hospitalized, are on antiretroviral therapy (ART), with successful viral suppression and immune reconstitution. In such cases, changes in CD4 counts detected in hospitalized patients are more likely to represent transient lymphocyte suppression than HIV disease progression. Similarly, in caring for PWH whose immune status is uncertain, a holistic assessment of immune status should start with history and physical exam, review of outpatient CD4 testing, and assessment of viral suppression and ART adherence. In cases where after these efforts, the patient's immune status remains unclear, and CD4 testing is likely to affect acute management, it is reasonable to obtain CD4 testing in consultation with a clinician with expertise in caring for PWH. When CD4 testing is sent in the hospitalized context, attention should be paid to both the CD4 count and the CD4% (which is less affected by acute stressors), and the CD4 testing should be interpreted in the clinical context in which it was sent.