Objectives: In 2018, Brazilian guidelines changed to recommend tuberculosis (TB) preventive therapy for all people with HIV and a CD4þ cell count 350 cells/ml or less, but only for those with a positive tuberculin skin test (TST) if CD4þ cell count is than 350 cells/ml. We determined the potential effectiveness of CD4þ-based guidelines for TB testing and preventive therapy. Design: Secondary analysis of the stepped-wedge, cluster-randomized THRio trial for isoniazid preventive therapy (IPT). Methods: We analyzed data from 4114 newly registered patients with HIV in 29 clinics followed until TB diagnosis, death, or administrative censoring. We compared incidence rates of TB and TB/death between CD4þ, TST, IPT, and antiretroviral therapy categories. Results: Initial CD4þ cell count was 350 cells/ml or less in 2138 (52%) and more than 350 cells/mlin 1976 (48%) patients. TST was performed for 2922 (71%), ofwhom657(16%) were TST-positive [278 (13%) CD4þ 350 vs. 379 (19%) CD4þ > 350]. A total of 619 (15%) received IPT and 2806 (68%) received antiretroviral therapy. For patients with CD4þ cellcount 350 cells/mlor less who did not receive IPT, the incidence rate of TB was 1.79/100 person-years (pys) and TB/death was 3.89/100 pys. For patients with CD4þ cell count more than 350 who did not receive IPT, the incidence rates of TB and TB/death were 0.57/100 and 1.49/100 pys for TST-negatives, and 1.05/100 and 1.64/100 pys for TST-unknowns. Conclusion: TB incidence was high among all patients who did not receive IPT, including those with CD4þ cell count more than 350 cells/ml and negative or unknown TST results. TB preventive therapy should be provided to all people living with HIV in medium burden settings, regardless of CD4þ cell count and TST status.