Coronary artery disease is currently one of the leading causes of mortality in patients with HIV. Severe left main disease (LMD) occurs in ~6% of the HIV-infected patients. We describe a case report of an atypical presentation of silent critical LMD in an HIV-infected patient who underwent a low-risk exercise stress test. The cardiovascular disease team should be vigilant for this latent phenomenon, specifically within this subpopulation despite the high Duke treadmill score.