Reliable prognostic factors that serve as a guide to follow-up of patients with locoregionally advanced nasopharyngeal carcinoma (NPC) have not yet been identified. We sought to investigate the prognostic implications of post-therapy PET in patients with NPC treated with chemoradiotherapy. Patients with locoregionally advanced NPC (stages III and IVa-b) who had completed primary curative treatment for 3 months were eligible. All of the patients underwent (18)F-FDG PET and conventional work-up (CWU) for the assessment of treatment response. A total of 165 patients were enrolled. Over a median follow-up of 58 months, 30 patients died and 41 had disease recurrence. The results of the 3-month post-therapy PET and total lesion glycolysis (TLG) of the primary tumor were independent predictors of overall survival. TNM tumor stage, TLG, and post-therapy PET findings were independently associated with disease-free survival (DFS). The results of post-therapy PET were more predictive of DFS than TNM tumor stage (P < 0.001 vs. P = 0.005). Among patients with stage IVa-b disease, there was a trend toward better 5-DFS rates in patients with a complete metabolic response (CMR) on PET than in those who showed a complete response in the CWU (5-year DFS = 70.7 vs. 63.1 %). Notably, the 1- and 2-year DFS rates were significantly better in the former group compared with the latter. In contrast, the results of post-therapy CWU were not a reliable predictor for DFS. The results of post-therapy PET are an important independent prognostic factor in locoregionally advanced NPC. CMR on PET is associated with better DFS rates and could serve as a guidance to individualize the surveillance protocols for patients with stage IVa-b disease.