OBJECTIVE: Investigation of the diagnostic yield of urine-based tuberculosis (TB) screening in patients with advanced HIV disease. DESIGN: A cross-sectional screening study. SETTING: HIV outpatient clinics and wards at two hospitals in Johannesburg, South Africa, between June 2015 and October 2017. PARTICIPANTS: Two hundred and one patients living with advanced HIV disease (CD4+ T-lymphocytes <100 cells/μl) attending healthcare facilities following cryptococcal antigen (CrAg) screening. INTERVENTION: Screening for TB using sputum for microscopy, culture, and Xpert MTB/Rif and urine for lipoarabinomannan (LAM) and Xpert Ultra. MAIN OUTCOME MEASURES: Proportion of positive results using each testing modality, sensitivity, and specificity of urine-based testing compared with culture, and survival outcomes during 6 months follow up. RESULTS: Urine was obtained from 177 of 181 (98%) participants and sputum from 91 (50%). Urine-based screening increased same-day diagnostic yield from 7 (4%) to 31 (17%). A positive urine test with either LAM or Xpert Ultra had 100% sensitivity (95% confidence interval, 59-100%) for detecting culture-positive TB at any site. Patients with newly diagnosed TB on urine-based screening were initiated on treatment and did not have excess mortality compared with the remainder of the cohort. CONCLUSION: Urine is an easily obtainable sample with utility for detecting TB in patients with advanced HIV disease. Combining urine and sputum-based screening in this population facilitates additional same-day TB diagnoses and early treatment initiation, potentially reducing the risk of TB-related mortality. Urine-based as well as sputum-based screening for TB should be integrated with CrAg screening in patients living with advanced HIV disease.