BACKGROUND: Intratumoral metabolic heterogeneity (MH) assessed by 18-fluorine fluorodeoxyglucose positron emission tomography/computed tomography (F-FDG PET/CT) has been recognized as a potential marker for chemotherapy resistance in solid tumors. However, research on MH in diffuse large B-cell lymphoma (DLBCL) is limited, and its specific relationship with the response to immunochemotherapy (IC) remains unclear. The objective of this study was to investigate optimal approaches for assessing intratumoral MH, and to analyze the association between PET/CT-based MH and end of treatment (EOT) response to IC in DLBCL. METHODS: This study retrospectively enrolled 304 newly diagnosed patients with DLBCL who underwent baseline F-FDG PET/CT scanning. Intratumoral MH was assessed by the method of the area under the curve of cumulative standardized uptake value (SUV) histogram (AUC-CSH), heterogeneity index (HI), and coefficient of variation (COV) of target lesion. Both univariate and multivariate logistic regression analyses were employed to investigate the association between intratumoral MH and the response to IC at the EOT. After adjusting for confounding factors, we utilized generalized additive model (GAM) and smooth curve fitting to explore potential nonlinear associations, and a binary logistic regression model was used to assess interactions within subgroups. RESULTS: A total of 70 patients (23%) developed primary progressive disease (PPD) at the EOT. Both AUC-CSH and HI were associated with the IC response in DLBCL, with AUC-CSH slightly superior to HI. No significant statistical difference was observed for COV. Univariate regression analysis revealed a significant association between AUC-CSH and the response to IC [odds ratio (OR)/per standard deviation (SD): 0.53; 95% confidence interval (CI): 0.38-0.73; P<0.001]. After adjusting for risk factors, this association remained significant (OR/per SD: 0.58; 95% CI: 0.40-0.85; P=0.006). The GAM indicated a negative linear association between AUC-CSH and the probability of developing PPD, with the top tertile group having the lowest likelihood of developing PPD (14.8%). CONCLUSIONS: In Chinese patients with DLBCL, an approximately negative linear correlation was observed between the AUC-CSH and the probability of developing PPD at the EOT of frontline IC. In simpler terms, as the degree of intratumoral MH increases, the probability of developing PPD also increases.