To assess the effect of a Bayesian penalised likelihood (BPL) reconstruction algorithm on the five-point scale (5-PS) score, response categorisation, and potential implications for therapy decisions after interim 2-[18F]-fluoro-2-deoxy- d- glucose (FDG) positron-emission tomography (PET)–computed tomography (CT) (iPET-CT) to guide treatment in classical Hodgkin's lymphoma (HL). The present study included new patients with HL undergoing iPET-CT from 2014–2019 after two cycles of doxorubicin (Adriamycin), bleomycin, vincristine, and dacarbazine (ABVD). Two reporters categorised response using the 5-PS and measured maximum standardised uptake values (SUV max) of the most avid tumour residuum, mediastinal blood pool, and normal liver with ordered subset expected maximisation (OSEM) and BPL reconstructions. Eighty-one iPET-CT examinations were reviewed. Compared with OSEM, BPL increased the 5-PS score by a single score in 18/81 (22.2%) patients. The frequency of potential treatment intensification by changing a score of 3–4 was 13.6% (11/81) and represented 25% (11/44) of patients with a score of 3 on OSEM. All 11 patients remained in remission without a change in therapy (mean 63 months) except one who required second-line treatment for refractory disease. Median SUV max of tumour residuum was significantly higher with BPL compared with OSEM (2.7 versus 2.4, p<< 0.0001), whilst liver SUV max was significantly lower for both reporters (up to 6.6%, p< 0.0001). BPL PET reconstruction increased the 5-PS score on iPET-CT in 22% of HL patients and can potentially result in unnecessary treatment escalation in over half of these patients. • BPL PET reconstruction increases the 5-PS score on iPET-CT in 22% patients with HL. • Unnecessary treatment intensification could occur in over half of these patients. • BPL increases tumour residuum SUV max and reduces liver SUV max. • Recommend review of BPL and OSEM reconstructions during iPET-CT interpretation. • Recommend use of OSEM reconstruction to clarify discordances in metabolic response. [ABSTRACT FROM AUTHOR]