Introduction: Primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) are both immune-mediated liver diseases, targeting biliary epithelial cells and hepatocytes, respectively. Due to their immune-mediated nature, some patients can develop overlap syndrome of AIH-PBC and have characteristics from both disease states. The aim of this study is to determine the risk factors that can predict the development of AIH-PBC overlap syndrome as compared to a related disorder, PBC-only disorder. Methods: This case-control study was performed at the Liver Associates of Texas Hepatology clinics in Houston, Texas. All patients diagnosed with AIH-PBC and PBC from January 2018 to May 2021 were included. Demographics and clinical parameters including patient characteristics and lab values were collected and compared. Patients were diagnosed with AIH-PBC overlap syndrome using liver biopsy and serological evidence. A binary logistic regression was used to determine the effects of demographic and clinical factors in the development AIH-PBC overlap syndrome compared to PBC-only controls. Results: A total of 136 PBC patients were included. Median age was 62 years, with 91.2% female. 36.8% were White, 14.7% Hispanic, 12.5% African American, 3.7% Asian, 2.2% Native American, and 30.1% unspecified. Of those 136 patients, 40 were identified to have PBC-AIH overlap syndrome (29.4%). No statistical differences were found in gender or ethnicity between the PBC-only and AIH-PBC overlap syndrome patients. Smoking was found to be significantly correlated with the presence of AIH-PBC overlap syndrome (p = 0.004). Accounting for BMI and alcohol use, patients with a smoking history were found to be 4.9 times (CI: 1.685-14.226) more likely to have AIH-PBC overlap syndrome than non-smokers. Alcohol use and BMI did not have a statistically significant effect on the presence of the AIH-PBC overlap syndrome. Conclusion: Smoking was found to be significantly correlated to the presence of the PBC-AIH overlap syndrome. This insight might provide support for counseling on smoking cessation in AIH or PBC patients who smoke. Further studies will be needed to determine other predictors and risk factors that might influence the development of AIH-PBC.Table 1.: Model Estimates of Possible Predictors for Overlap Syndrome in Primary Biliary Cholangitis Patients. Estimates represent log odds of patients with AIH-PBC overlap syndrome vs. PBC patients.