Background: Breast cancer is the most commonly diagnosed cancer and the second most leading cause of death next to cervical cancer in Ethiopia. An economic burden of breast cancer is a considerable issue in most middle and low income countries, especially in Ethiopia, where there is high out-of-pocket expenditure for health. Objectives: To estimate Economic burden of breast cancer patients on chemotherapy attending at Tikur Anbessa Specialized Teaching Hospital (TASH) and to determine Predictors for variation in patient related cost of breast cancer patients on chemotherapy. Methods: The Cost of illness study on 349 breast cancer cases was carried out at Tikur Anbessa Specialized Teaching Hospital (TASH) using cross sectional study design. A Simple random sampling method was used to select study participants. As a semi-structured questionnaire was used to collect data, mean, median and standard deviation were used to calculate direct cost indirect cost and companion side costs. Multiple linear regression analysis was employed to analyze the separate effects of the various predictor variables on cost of treatment. Results: The average outpatient direct cost at Tikur Anbessa Specialized Teaching Hospital for breast cancer on chemo-therapy was 24953.45 ETB ($1188.26) SD (=24874.77{$1184.51}). Direct medical cost comprised the largest part (mean=18753.41 ETB (893.02 USD) (SD=18860.95 ETB) $898.14). Mean expenses for non-prescribed remedies was, 6200.00 birr ($295.24), takes the lion share of direct nonmedical cost followed by expense for transportation (mean=3568.31 ETB {$169.92). Conclusion: This study shows that the financial burden of breast cancer is substantial and overwhelming for both patients and their families. Outpatient treatment cost was found to be dependent on number of employed household members, number of facility visited. Longer duration of inpatient hospital stay and stages of breast cancer is associated with inpatient cost and indirect cost.