PURPOSE: Vaccine-associated hypermetabolic lymphadenopathy (VAHL) is frequently observed on [F]FDG PET-CT following BNT162b2 administration. Recent data suggest a prominent B cell germinal-center (GC) response elicited by mRNA vaccines in draining lymph nodes. Thus, in this study we aimed to explore the correlation between VAHL and humoral immunity as reflected by post-vaccination serologic testing and by comparing the incidence of VAHL between lymphoma patients treated recently with B cell depleting therapy and those that were not. METHODS: A total of 137 patients with hematologic malignancy that had post-vaccination [F]FDG PET-CT were included (All-PET group), 86 received both vaccine doses before imaging (PET-2 group). Their VAHL status and grade on imaging were recorded. Among 102 lymphoma patients, 34 (33.3%) were treated during the year prior vaccination with anti-CD20 antibody containing therapy. A subgroup of 54 patients also underwent serologic testing 2-3 weeks after the booster dose, and their anti-spike titers were recorded and graded as well. RESULTS: The overall incidence of VAHL in patients with hematologic malignancy was 31.4%. The 34 lymphoma patients treated during the year prior vaccination with anti-CD20 antibody containing therapy had significantly lower rates of VAHL comparted with all other lymphoma patients (8.8 versus 41.2% in all-PET patients, Pv < 0.01). VAHL rates were 10% in patients with negative serology, 31.3% in patients with low anti-spike titers, and 72.2% in patients with high anti-spike titers. The positive predictive values of VAHL were 90 and 93.3% in all-PET and PET-2 patients, respectively. A positive statistically significant correlation was found between VAHL and serology ranks in All-PET patients (r = 0.530, Pv < 0.001), and stronger correlation was found in PET-2 patients (r = 0.642, Pv < 0.001). CONCLUSION: VAHL on [F]FDG PET-CT of patients with hematologic malignancy may reflect GC B cell proliferation and an effective humoral response elicited by BNT162b2 vaccine.