BackgroundDiffuse large B-cell lymphoma (DLBCL) is a clinically heterogeneous subtype of non-Hodgkin lymphoma. While R-CHOP improves prognosis, relapse persists in some patients. Jiedu Xiaoliu Formula (JDXLF), a traditional Chinese medicine (TCM) compound, may synergize with chemotherapy. This study aimed to evaluate the impact of JDXLF’s on progression-free survival (PFS) and immune modulation in DLBCL.MethodsThis retrospective cohort study included 188 patients diagnosed with DLBCL between January 2014 and December 2023 at Shanghai Municipal Hospital of Traditional Chinese Medicine. Patients were stratified into chemotherapy alone (n = 76), chemotherapy + JDXLF (n = 54), and post-chemotherapy JDXLF maintenance (n = 58). Kaplan–Meier survival, LASSO, and multivariate Cox regression were applied to evaluate progression-free survival (PFS) and prognostic factors. Secondary endpoints included overall response rate (ORR), TCM symptom scores, immune biomarkers, and adverse events.ResultsMedian PFS was significantly longer in the chemotherapy + JDXLF group (57 months) and JDXLF maintenance group (51 months) compared with chemotherapy alone (39 months; log-rank P < 0.05). Six-month, 1-year, and 2-year PFS rates were consistently higher in both JDXLF groups (all P < 0.05). Cox analysis confirmed that concurrent JDXLF independently reduced the risk of progression (HR = 0.54; 95% CI: 0.30–0.95; P = 0.031). ORR improved with JDXLF (85.2% vs. 76.4% with chemotherapy alone). At 24 months, JDXLF groups showed significantly lower TCM symptom scores (median 5–7 vs. 10; P < 0.001) and reduced monocytic myeloid-derived suppressor cell (M-MDSC) levels (0.08–0.09 vs. 0.15; P < 0.001).ConclusionJiedu Xiaoliu Formula combined with chemotherapy may improve progression-free survival and reduced immunosuppressive M-MDSC levels in DLBCL patients.