Background: Psychiatric disturbances in chronic HCV infected patients under treatment by Pegylated-interferon and ribavirin combined therapy (PEG-IFN/Rib) still show worldwide controversy and no sufficient studies address this problem in Upper Egypt. Aim of the study: to detect the pattern and prevalence of psychiatric disturbances in chronic HCV infected (CHC) patients under PEG-IFN/Rib and the risk factors for these disturbances. Patients and methods: 167 CHC patients were recruited from the virology clinic in Sohag University Hospital between November 2012 and January 2015; 100 cases of them completed the study. Patients were assessed generally and psychologically before initiation and after 12 weeks of therapy using Symptom Checklist-90-Revised (SCL-90-R), The Mini International Neuropsychiatric Interview version 5 (MINI), Hamilton Rating Scale for Depression (HAM-D), Hamilton Anxiety Rating Scale (HAM-A) , and The Structured Interview for the Five-Factor Model (SIFFM) scales. Results: Major depressive disorder (MDD) was the only detected syndrome based on MINI in 35% of cases; but significant subsyndromal depression were detected in further 43% of cases by HAMD, & significant anxiety changes from base line HAMA results (differences in mean= -4.620±3.902, P<0.001) with further detected significant increase in somatization, interpersonal sensitivity & Hostility by SCL90-R,in addition to depression and anxiety domains. Suicide risks were low, with no case stopped treatment. Age (more elderly), past history and family History of Psychiatric disorders, pre-treatment basal depressive symptoms, anxiety score, somatization score & Hostility scores were a significant predictors for occurrence of MDD. Conclusions: Depression And anxiety are the main disturbances after 12wks of PEG-INF/Rib therapy. Pretreatment screening for depressive symptoms, past & family history of psychiatric illness will help to identify those at high risk of MDD under IFN based therapy for HCV.