Introduction: Malignant cells have built-in mechanisms to protect themselves from the effects of chemotherapeutic agents. P53, via catalase, reduces reactive oxygen species (ROS) accumulation. P53 is mutated in almost all cancers, resulting in the accumulation of ROS and pro-tumorigenic signals. ROS can cause cell death through necrosis, apoptosis, or necroptosis. This study aimed to investigate the catalase-expressing cells and the necrotic area in osteosarcoma chemotherapeutic response. Methods: This was observational analytic research using a retrospective design. The Huvos grades I, II, and III-IV, which indicate distinct degrees of tumor differentiation and aggressiveness, were compared. Formalin-fixed paraffin-embedded (FFPE) osteosarcoma tissue samples were histopathologically and immunohistochemically examined. Results: The study of 27 samples revealed that 8 had a poor response, 14 had a moderate response, and 5 had a good response to chemotherapy. The percentage of necrotic area differed significantly (p=0.000) across treatment response groups. In contrast, there were no significant differences (p>0.05) in the number of catalase-expressing cells across treatment response groups.