Purpose This work aims to identify intratumoral habitats with distinct heterogeneity based on 2-deoxy-2-[F-18]fluro-d-glucose positron emission tomography (PET)/X-ray computed tomography (CT) imaging, and to develop a subregional radiomics approach to predict progression-free survival (PFS) in patients with nasopharyngeal carcinoma (NPC). Procedures In total, 128 NPC patients (85 vs. 43 for primary vs. validation cohorts) who underwent pre-treatment PET/CT scan were enrolled retrospectively. Each tumor was partitioned into several phenotypically consistent subregions based on individual- and population-level clustering. For each subregion, 202 radiomics features were extracted to construct imaging biomarker for prognosis via Cox's proportional hazard model combined with forward stepwise feature selection. Relevance of imaging biomarkers and clinicopathological factors were assessed by multivariate Cox regression analysis and Spearman's correlation analysis. To investigate whether imaging biomarkers could provide complementary prognosis information beyond existing predictors, a scoring system was further developed for risk stratification and compared with AJCC staging system. Results Three subregions (denoted as S1, S2, and S3) were discovered with distinct PET/CT imaging characteristics in the two cohorts. The prognostic performance of imaging biomarker S3 outperformed the whole tumor (C-index, 0.69 vs. 0.58; log-rank test, p < 0.001 vs. p = 0.552). Imaging biomarker S3 and AJCC stage were identified as independent predictors (p = 0.011 and 0.042, respectively) after adjusting for clinicopathological factors. The scoring system outperformed the traditional AJCC staging system (log-rank test, p < 0.0001 vs. p = 0.0002 in primary cohort and p = 0.0021 vs. p = 0.0277 in validation cohort, respectively). Conclusions Subregional radiomics analysis of PET/CT imaging has the potential to predict PFS in patients with NPC, which also provides complementary prognostic information for traditional predictors.