Abstract BACKGROUND: The disease of sickle cell anemia (SCA) is an inherited blood disease that causes several complications, and oxidative stress (OS) may play a very important role in its complications and pathophysiology. OBJECTIVE: The aims of the study is to evaluate the possible pathophysiological role of some antioxidant and oxidant biomarkers within SCA patients and to evaluate the correlation of OS and atherogenic index of plasma (AIP) to predict the cardiovascular risk in SCA subjects. MATERIALS AND METHODS: A case–control research includes three study groups: SCA patients, sickle cell trait (SCT) subjects, and healthy controls (HCs). All study groups were evaluated for their serum catalase (CAT), serum superoxide dismutase (SOD), glutathione peroxidase (GPx), and malondialdehyde (MDA) as well as plasma triglycerides and high-density lipoprotein cholesterol. Data were collected, tabulated, and statistically analyzed using (SPSS) version 31 program. The frequencies, relative frequencies, and means were obtained as descriptive methods. The associations among parameters were obtained using the Chi-square statistical method. RESULTS: The results revealed significantly lower levels of serum SOD and GPx among sickle cell disease (SCD) and SCT subjects than the HCs, whereas the inverse findings were reported for CAT and AIP. However, the MDA results revealed a significantly higher level in SCD patients compared to SCT and HC. Furthermore, the levels of SOD and MDA were positively associated in all study groups, and the levels of GPx and MDA were negatively correlated in SCD and SCT groups. The AIP was positively correlated with MDA in the SCT group and negatively correlated with CAT in the SCD group. CONCLUSIONS: The conclusion of the study indicated the presence of an OS and antioxidant compensatory status in patients with SCD and the SCT subjects. The altered biomarkers in SCA patients made it clear that the impairment and generation of OS in this disease, as well as antioxidant biomarkers, are contributory factors toward cellular redox homeostasis. This addressed the aim of the study.