Abstract This research investigates the effects of four oral antiretroviral drugs on erythrocyte catalase activity and the relative stability of the erythrocyte membrane in wistar rat. Sixty (60) rats with average body weight 100 grams were allowed to acclimatize for two weeks and were distributed into four (4) groups. Blood samples were collected from the experimental animals by cardiac puncture. Catalase activity was determined spectrophotometrically, allowing the enzyme to split H2O2 for different periods of time. The osmotic fragility of the erythrocytes was determined by measuring the release of haemoglobin from blood added to tubes containing serially diluted phosphate buffered saline (PBS, pH 7.4). Results revealed that catalase activity decreases significantly (p<0.05) in the presence of lamivudine (from 17.13±3.01to 16.40±2.04) efavirenz (from 17.05±1.18 to 16.41±1.11) abacavir sulfate (from 16.36±0.28 to 15.60±2.18); nevirapine caused non-significant (p>0.05) decrease. All drugs investigated increased the mean corpuscular fragility of rat erythrocyte membrane. Efavirenz and abacavir caused significant (p<0.05) increases from 0.34±0.03 to 0.543±0.10 and 0.34±0.00 to 0.45±0.05 respectively, while the increases from 0.33±0.0 to0.40±0.02 and from 0.34±0.06 to 0.42±0.08 respectively in the presence of nevirapine and lamivudine were not significant (p>0.05). All the drugs investigated destabilized the rat erythrocyte. All drugs investigated may reduce the ability of the erythrocyte to withstand oxidative stress, and they have the capacity to increase the permeability of the erythrocyte membrane and can compromise the integrity and functionality of the erythrocyte.