Purpose: This study was to identify factors predicting the occurrence of depression among patients with hepatitis C treated with Peg-interferon. Methods: The subjects were 134 patients treated with Peg-interferon after the diagnosis with hepatitis C at the D University Hospital and 3 hospitals located in Busan, South Korea. The predictors of depression were identified by measuring the general characteristics of the subjects and their disease-related characteristics, social support, sleep disorders, and degree of side effects by interferon. The data were analyzed with a t-test, ANOVA, and logistic regression using the SPSS/WIN 18.0 program. Results: Sixty-six point four percent of the subjects suffered from mild to more severe depression. Fatigue, hair loss, itching, and sleep disorders turned out to be significant predictors. In addition, the explanatory power of these variables for the occurrence of depression was 70%. Conclusion: Sleep disorders and drug side effects were determined to have significant influence on the development of depression in hepatitis C patients treated with Peg-interferon. Therefore, the development of nursing intervention programs aimed to prevent depression by effectively managing sleep disorders and side effects is mandated in future to help the given population.