Three patients with human immunodeficiency virus (HIV) infection presented with QT, prolongation (> 440 ms) and torsades de pointes. We sought to evaluate the etiology of the long QT syndrome in these patients without previously identified causes for QT, prolongation, and determine the prevalence among patients with HIV infection. The three index patients underwent: (1) left stellate ganglion block; (2) beta-blocker challenge; and (3) electrocardiographic stress testing. QTc interval was measured before and after intervention. We undertook a retrospective analysis of prevalence of QTC prolongation among all patients with computerized ECGs over a 6-month period at one institution and compared it to the prevalence in hospitalized patients with HIV disease. Thirty-four thousand one hundred eighty-one patients with computerized ECGs were screened for QTc prolongation. Forty-two hospitalized patients with HI disease had computerized ECG during the same 6-month period. In the three index patients, the QTc failed to shorten with left stellate ganglion blockade, beta-blocker challenge, or stress testing, suggesting an acquired form of the long QT syndrome in these patients with HIV disease. None had previously recognized acquired causes of QT, prolongation. Mexiletine hydrochloride was useful in preventing recurrences of torsades de pointes. We observed a 7.0% prevalence of QT, prolongation among all patients screened. Hospitalized patients with HIV disease (n = 42) during this same period, demonstrated an increased prevalence of QT, prolongation (28.6%, P = 0.002). Patients with HIV disease have a significantly higher prevalence of QTc prolongation than a general hospital-based population, may have an unrecognized acquired form of the long QT syndrome, and are at risk for torsades de pointes.