Abstract: Background　Currently, salvage therapy for classical hodgkin lymphoma (cHL) resistant to PD-1 inhibitors remains predominantly based on chemotherapy, chemotherapy combined with immunotherapy, or targeted regimens. This treatment paradigm is often associated with high rates of adverse events and imposes a significant financial burden on patients, while also lacking sufficient real-world evidence. The low-dose decitabine plus PD-1 inhibitor (DP regimen) is hypothesized to enhance antitumor efficacy through synergistic effects with a more favorable toxicity profile. However, real-world data remain scarce for cHL patients who have failed first-line PD-1 inhibitor therapy. Objective　To evaluate the clinical benefits of the DP regimen compared to other salvage therapies in cHL patients who experience treatment failure after their first PD-1 inhibitor therapy in the real-world setting, and explore its effectiveness, safety, quality of life, and cost-effectiveness as a potential first-choice "chemotherapy-free" option. Methods　Clinical data about cHL patients admitted to Chinese PLA General Hospital from June 2016 to July 2023 who received subsequent salvage treatment after the first failed PD-1 inhibitor treatment were retrospectively collected. According to the treatment plan, they were divided into group A (DP regimen group) and group B (other conventional salvage regimens). Group A regimen consisted of low-dose decitabine combined with PD-1 inhibitor; group B regimen included monotherapy chemotherapy, chemotherapy combined with PD-1 inhibitor, targeted therapy, and others. The complete response rate (CRR), objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), duration of response (DOR), adverse event (AE incidence), quality of life (QLQ-HL27 score), and treatment costs were compared between the two groups. Results　This study included 82 patients with classical Hodgkin lymphoma (cHL) who had failed initial PD-1 inhibitor therapy. Among them, 52 patients subsequently received the DP regimen, while 30 patients received other conventional salvage regimens. Baseline characteristics between the two groups showed no statistically significant differences in terms of gender, age, clinical stage, histologic subtype, or B symptoms (all P>0.05), indicating comparability. Regarding safety, the incidence of adverse events in the DP regimen group was significantly lower than that in the conventional salvage therapy group (48.1% vs 96.7% RR=0.50, 95% CI: 0.35 - 0.71, P＜0.001). Economic analysis revealed significantly lower median treatment costs per cycle in the DP regimen group (88.5% of patients incurred costs below 6 000 yuan, compared to only 23.3% in the other conventional salvage regimen group, which included individuals with costs exceeding 20 000 yuan). Quality of life scores were superior in the DP regimen group. Regarding efficacy metrics, the two groups showed no significant differences in ORR (P=0.672), DCR (P=0.093), PFS (P=1.000), DOR (P=0.651), median PFS (18.2 months vs 14.1 months, P=1.000) and median DOR (19.9 months vs 20.0 months, P=0.651). Conclusion　The results of this study show that for patients with classical Hodgkin's lymphoma who have failed the first PD-1 inhibitor treatment, low-dose decitabine combined with PD-1 inhibitor as a salvage treatment regimen can significantly reduce the incidence of adverse events, improve the quality of life of patients, and reduce the economic burden while maintaining the similar short-term efficacy with conventional salvage regimens.