OBJECTIVES: To evaluate the diagnostic accuracy of and reduction in diagnostic delay attributable to a clinical algorithm used for the diagnosis of smear-negative pulmonary tuberculosis (SNPTB) in HIV-infected adults. DESIGN: An algorithm was designed to facilitate clinicoradiological diagnosis of pulmonary TB (PTB) in HIV-infected smear-negative adult patients. A folder review was performed on the first 58 cases referred for empirical TB treatment using this algorithm. SETTING: Nolungile HIV Clinic, Site C, Khayelitsha. SUBJECTS: Subjects included 58 HIV-infected adult patients with suspected PTB consecutively referred to the local TB clinic for outpatient TB treatment using this algorithm between 12 February 2004 and 30 April 2005. OUTCOME MEASURES: Outcome measures were response of C-reactive protein, haemoglobin, weight and symptoms to TB treatment, and TB culture result. Diagnostic delay (in days) was calculated. RESULTS: Thirty-two of the 58 patients (55%) had positive TB cultures (definite TB). Initiation of TB treatment occurred on average 19.5 days before the positive culture report. A further 21 patients (36%) demonstrated clinical improvement on empirical treatment (probable/possible TB). Two patients did not improve and subsequently died without a definitive diagnosis. Three patients defaulted treatment. CONCLUSIONS: SNPTB is more common in HIV-infected patients and leads to diagnostic delay. This algorithm allowed for earlier initiation of TB treatment in HIV-infected patients presenting with symptoms of PTB and negative smears or nonproductive cough in a high TB incidence setting.