Objectives: To investigate changes after adding L-carnitine and silymarin compared to anthracycline chemotherapy alone on the health-related quality of life (HRQoL) of women with breast cancer receiving anthracycline-based chemotherapy. Methods: A prospective, randomized comparative, study that included 120 women with breast cancer who received anthracycline in their chemotherapeutic regimen. Patients were divided into three groups, anthracycline alone (control group), chemotherapy and l-carnitine (l-carnitine group), and chemotherapy plus silymarin (silymarin group). HRQoL was evaluated using the EORTC QLQ-C30 and EORTC QLQ-BR23 instruments 7 days before chemotherapy and after the third month of chemotherapy. Results: On the application of (EORTC QLQ-C30), there was a significant decrease in global health status/QoL score, functional scale scores from baseline to after three months (P≤0.001) within the control group and a significant increase in symptom scale scores from baseline to after three months.  In l-carnitine and silymarin groups, there was a non-significant difference in the scale scores. On the application of (EORTC QLQ-BR23), there was a significant decrease in functional scale scores (p≤0.001) within the control group and a significant increase in symptom scale scores (p≥0.05). In the l-carnitine and silymarin groups, there was a non-significant difference in functional scale scores from baseline to after three months (p≥0.05). Conclusions: QOL was negatively affected by chemotherapy. For BC cases, HRQoL becomes typically worse during the third month of chemotherapy compared with the pretreatment duration. The addition of l-carnitine and silymarin to anthracycline-based chemotherapy showed improvement in the health-related quality of life of cancer patients.