Microbial culture is the gold standard for determining the effectiveness of tuberculosis treatment. End-of-treatment (EOT) FDG-PET/CT findings are variable among patients with negative microbial culture after completing standard regimen of anti-tuberculous treatment (ATT) with some patients having a complete metabolic response to treatment while others have residual metabolic activity (RMA). We herein determine the impact of findings on EOT FDG-PET/CT on tuberculosis relapse in patients treated with a standard regimen of ATT for drug-sensitive pulmonary tuberculosis (DS-PTB). Patients who completed a standard regimen of ATT for DS-PTB and were declared cured based on negative clinical and bacteriological examination were prospectively recruited to undergo EOT FDG-PET/CT. Images were assessed for the presence of RMA. Patients were subsequently followed-up for six months looking for symptoms of tuberculosis relapse. When new symptoms develop, relapse was confirmed with bacteriological testing. Repeat FDG-PET/CT was done in patients who relapsed. Fifty-three patients were included, mean age = 37.81 ± 11.29 years with 62% males and 75% human immunodeficiency virus (HIV)-infected. RMA was demonstrated in 33 patients (RMA group) while 20 patients had a complete metabolic response to ATT (non-RMA group). There was a higher prevalence of lung cavitation in the RMA group ( = 0.035). Both groups were not significantly different regarding age, gender, presence of HIV-infection, body mass index or hemoglobin level (p>0.05). On follow-up, no patients in the non-RMA group developed TB relapse. Three patients in the RMA group developed relapse. All patients who developed tuberculosis relapse had bilateral disease with lung cavitation. A negative EOT FDG-PET/CT is protective against tuberculosis relapse. Nine percent of patients with RMA after ATT may experience tuberculosis relapse within six months of completing ATT. Bilateral disease with lung cavitation is prevalent among patients with tuberculosis relapse.