Pakistan ranks fifth among high tuberculosis (TB) burden countries and also has seventh highest burden for diabetes mellitus (DM). DM increases the risk of developing TB and contributes to adverse TB treatment outcomes hence screening and integrated management for both diseases in high burden countries is suggested. Computer-Aided Detection for TB (CAD4TB) can potentially be used as triage tool in low resource settings to pre-screen individuals for Xpert MTB/RIF testing. The aim of this study was to evaluate the diagnostic accuracy and performance of CAD4TB software in people with diabetes (PWD) enrolled in a TB screening program in Karachi, Pakistan. A total of 694 individuals with a diagnosis of DM (of whom 31.1% were newly diagnosed) were screened with CAD4TB and simultaneously provided sputum for Xpert MTB/RIF testing. Of the 74 (10.7%) participants who had bacteriologically positive (MTB+) results on Xpert testing, 54 (73%) had a CAD4TB score >70; and 155 (25%) participants who tested MTB-negative had scores >70. The area under the receiver operator curve was 0.78 (95% CI: 0.77-0.80). Our study findings indicate that CAD4TB offers good diagnostic accuracy as a triage test for TB screening among PWD using Xpert MTB/RIF as the reference standard.