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Background • Non-alcoholic fatty liver disease (NAFLD) has reached pandemic proportions globally, particularly affecting individuals with type 2 diabetes mellitus (T2DM). Objective • Our study aims to elucidate the diagnostic value of fasting C-peptide in combination with insulin resistance for assessing hepatic fibrosis in patients with T2DM and comorbid NAFLD. Design • This was a retrospective study. Setting • The study was conducted at the Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine. Participants • The research involved 76 type 2 diabetes mellitus patients with nonalcoholic fatty liver disease, diagnosed at our hospital from April 2020 to October 2022. Patients were categorized into the non-progressive hepatic fibrosis group (n = 64) and progressive hepatic fibrosis group (n = 12) based on fibrosis-4 value. Interventions • General data, systolic/diastolic blood pressure, fasting plasma glucose, fasting C-peptide, fasting insulin, glycosylated hemoglobin, uric acid, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, aspartate transaminase, alanine transaminase, and γ-glutamyl transferase were collected. Insulin resistance was calculated using a designated formula. Primary Outcomes Measures • The predictive impact of fasting C-peptide in combination with insulin resistance was evaluated through receiver operating characteristic curves. Results • The age, body mass index, fasting C-peptide, fasting insulin, aspartate transaminase, and insulin resistance showed a significant increase in the progressive hepatic fibrosis group compared to the non-progressive group (P = .006, P = .014, P <.001, P < .001, P = .004, and P = .021). The combination's sensitivity demonstrated an elevation compared to fasting C-peptide or insulin resistance alone (P = .005). Conclusions • Fasting C-peptide in combination with insulin resistance proves to have a substantial predictive impact on hepatic fibrosis in type 2 diabetes mellitus patients with nonalcoholic fatty liver disease, holding valuable clinical diagnostic potential. [ABSTRACT FROM AUTHOR]