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Summary: We evaluated the impact of liposomal doxorubicin (NPLD) supercharge‐containing therapy on interim fluorodeoxyglucose positron emission tomography (interim‐FDG‐PET) responses in high‐risk diffuse large B‐cell lymphoma (DLBCL) or classical Hodgkin lymphoma (c‐HL). In this phase II study (2016–2021), 81 adult patients with advanced‐stage DLBCL (n = 53) and c‐HL (n = 28) received front‐line treatment with R‐COMP‐dose‐intensified (DI) and MBVD‐DI. R‐COMP‐DI consisted of 70 mg/m2 of NPLD plus standard rituximab, cyclophosphamide, vincristine and prednisone for three cycles (followed by three cycles with NPLD de‐escalated at 50 mg/m2); MBVD‐DI consisted of 35 mg/m2 of NPLD plus standard bleomycin, vinblastine and dacarbazine for two cycles (followed by four cycles with NPLD de‐escalated at 25 mg/m2). Patients underwent R‐COMP‐DI and MBVD‐DI with a median dose intensity of 91% and 94% respectively. At interim‐FDG‐PET, 72/81 patients (one failed to undergo interim‐FDG‐PET due to early death) had a Deauville score of ≤3. At end of treatment, 90% of patients reached complete responses. In all, 20 patients had Grade ≥3 adverse events, and four of them required hospitalisation. At a median 21‐months of follow‐up, the progression‐free survival of the entire population was 77.3% (95% confidence interval 68%–88%). Our data suggest that the NPLD supercharge‐driven strategy in high‐risk DLBCL/c‐HL may be a promising option to test in phase III trials, for improving negative interim‐FDG‐PET cases incidence. [ABSTRACT FROM AUTHOR]