Measurement of health-related quality-of-life (HRQL) captures dimensions of health not otherwise assessed. However, HRQL measurement is time-consuming and difficult to incorporate into a routine clinical care setting. The purpose of this study was to assess the construct validity, discriminative ability, and feasibility of administering a single-item health status measure (EVGGFP) of HRQL rating health as excellent, very good, good, fair, or poor among HIV-infected patients in routine clinical care. Patients attending an urban HIV specialty clinic completed a survey assessing their current symptom burden, HRQL as measured by EVGGFP and by a 7-domain, 21-item HRQL instrument (HRQL-21), and sociodemographic factors (n = 269). Patients were predominantly men (91%), 27% reported a history of intravenous drug use, and over half had some college education. We used multiple regression analysis to examine the association between HRQL assessed by EVGGFP and the HRQL-21. We compared the discriminative ability of EVGGFP and the HRQL-21 to detect differences in CD4 cell count, plasma HIV-1 RNA level, and symptom burden. We found that HRQL scores determined by EVGGFP were significantly associated with domain scores from the HRQL-21 (adjusted R2 0.42-0.69). The discriminative ability of EVGGFP was equivalent to that of the HRQL-21. EVGGFP had high sensitivity and low to moderate specificity in identifying patients with poor overall HRQL who might benefit from more comprehensive evaluation of multiple HRQL domains. EVGGFP can be used to assess health status among HIV-infected patients in routine clinical care and may be useful in settings in which comprehensive HRQL assessment is not practical.