Background: Though sickle cell anaemia (SCA) is known to promote oxidative stress, there is paucity of information on the relationship between oxidative stress and vaso-occlusive crisis (VOC). Objective: This study was undertaken to evaluate the relationship of oxidative stress and antioxidant response with VOC in SCA. Methods: A cross-sectional case-control study was carried out at University of Nigeria Teaching Hospital (UNTH), Itu- ku-Ozalla, Enugu Nigeria involving 116 individuals which included 36 SCA subject, 40 sickle cell carriers (AS) and 40 healthy individuals (AA). Baseline information as well as the frequency of VOC was obtained from the participants and anaemia as well as oxidative stress and antioxidant indices were assessed in blood. Results: Anaemia was prevalent (88.9 %) in SCA individuals compared to AS (52.5%) and AA (47.5 %) individuals. Nitric oxide scavenging (NOS) and superoxide dismutase (SOD) activities as well as glutathione level were significantly (p<0.005) lower while catalase activity was higher in SCA individuals compared to controls (AA and AS). Higher malondialdehyde (MDA) level was associated with very severe VOC while low level of NOS activity was associated with severe VOC in SCA individuals. Conclusion: Sickle cell anaemia exhibited oxidative stress and alteration in the levels of antioxidant indices which was pos- sibly associated with vaso-occlusive crisis. Keywords: Sickle cell anaemia; oxidative stress; antioxidant; vaso-occlusive crisis.