Abstract: OBJECTIVE To explore the relationship between high mobility group box-1 protein (HMGB-1), monocyte chemoattractant protein-1 (MCP-1) and the severity and prognosis of chronic glomerulonephritis (CGN). METHODS A total of 100 patients with CGN from Xi'an Kidney Diseases Hospital of Traditional Chinese Medicine from Feb. 2022 to Feb. 2023 were randomly selected. They were divided into chronic kidney disease (CKD) stages 1-2 (n=64) and CKD stages 3-5 (n=36). These groups were further divided into a favorable prognosis group (n=68) and a poor prognosis group (n=32). The diagnostic efficacy of HMGB-1 and MCP-1 for severity and their predictive value for poor prognosis were analyzed. RESULTS Compared with CKD stages 1-2, levels of HMGB-1, MCP-1, β2-microglobulin (β2-MG), cystatin C (Cys-C), serum creatinine (Scr), white blood cells (WBC), neutrophils (NEU), C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, transforming growth factor-β (TGF-β) and IL-8 were increased in CKD stages 3-5 (P<0.05), while estimated glomerular filtration rate (eGFR) and IL-10 were decreased (P<0.05). As CKD stages advanced, the diagnostic efficacy of HMGB-1, MCP-1 and their combination for severity increased, with the combination of HMGB-1 and MCP-1 demonstrating the highest diagnostic efficacy. Model 2 (including HMGB-1 and MCP-1) showed improved AUC, IDI and NRI, as well as better goodness-of-fit than Model 1 (excluding HMGB-1 and MCP-1) (P<0.05). Elevated levels of HMGB-1 and MCP-1 enhanced the positive association between CGN severity and poor prognosis, and there was a nonlinear dose-response relationship between these markers and poor prognosis (P<0.001). CONCLUSIONS Serum HMGB-1 and MCP-1 levels increase with the progression of CKD stages in patients with CGN. The inclusion of these two markers in a model can enhance the predictive value for disease prognosis. Moreover, both exhibit a nonlinear dose-response relationship with poor prognosis, serving as effective markers for diagnosing disease severity and predicting poor prognosis.