Microbial culture is the gold standard for determining the effectiveness of tuberculosis treatment. End-of-treatment (EOT) 18F-FDG PET/CT findings are variable among patients with negative microbial culture results after completing a standard regimen of anti-tuberculous treatment (ATT), with some patients having a complete metabolic response to treatment whereas others have residual metabolic activity (RMA). We herein determine the impact of findings on EOT 18F-FDG PET/CT on tuberculosis relapse in patients treated with a standard regimen of ATT for drug-sensitive pulmonary tuberculosis (DS-PTB). METHODS : Patients who completed a standard regimen of ATT for DS-PTB and were declared cured based on a negative clinical and bacteriologic examination were prospectively recruited to undergo EOT 18F-FDG PET/CT. Images were assessed for the presence of RMA. Patients were subsequently followed up for 6 mo looking for symptoms of tuberculosis relapse. When new symptoms developed, relapse was confirmed with bacteriologic testing. Repeat 18F-FDG PET/CT was done in patients who relapsed. RESULTS : Fifty-three patients were included (mean age, 37.81 ± 11.29 y), with 62% being male and 75% HIV-infected. RMA was demonstrated in 33 patients (RMA group), whereas 20 patients had a complete metabolic response to ATT (non-RMA group). There was a higher prevalence of lung cavitation in the RMA group (P 5 0.035). The groups did not significantly differ in age, sex, presence of HIV infection, body mass index, or hemoglobin level (P . 0.05). On follow-up, no patients in the non-RMA group developed tuberculosis relapse. Three patients in the RMA group developed relapse. All patients who developed tuberculosis relapse had bilateral disease with lung cavitation. CONCLUSION : A negative EOT 18F-FDG PET/CT result is protective against tuberculosis relapse. Nine percent of patients with RMA after ATT may experience tuberculosis relapse within 6 mo of completing ATT. Bilateral disease with lung cavitation is prevalent among patients with tuberculosis relapse.