Background: In recent years the survival rates for children diagnosed with cancer has increased as result of successful treatment. Evaluation of health related quality of life during the process of treatments is important for recognition of acute dysfunction related to therapy and disease. Aim: Aim of the study is to identify the health-related quality of life in pediatric cancer patients and to detect the potential predictors of a total quality of life and its domains. Materials and Methods: It is a cross-sectional study done on convenient sample of pediatric cancer patients. Their diagnosis was confirmed at pediatric hematology clinic and day care unit at King Abdulaziz University Hospital, Jeddah, Saudi Arabia. Results: A total number of 51 children participated in this study, their age ranging from 8-15 years with mean 10.15± 2.52. Hematological malignancies represented 70.5% of the sample, with the highest percentage for acute lymphocytic leukemia (45%). The mean value of the total quality of life is 73.48, which is referred to as a good quality of life. The best scores of subscales were cognitive problems (92.54), communication (82.67), and nausea (76.86), otherwise poorer score was detected. Although the value of total quality of life was relatively good however visiting the hospital more than 3 times per month, male gender, duration of therapy and duration of diagnosis more associated with more pain and hurt, great worry and treatment anxiety. Conclusion: Higher frequency of hospital visits, male gender, longer duration of diagnosis, longer duration of therapy, and increased intensity of therapy were all associated with more pain and hurt, great worry, nausea, and treatment anxiety which reflect a poor quality of life among the study group.