This descriptive study investigates in a rabbit model of atherosclerosis (i) the extent of atherogenesis induced by cyclosporine A (CsA) or hyperlipidemia alone or in combination and (ii) whether thymoquinone (TQ), a known herbal antioxidant, offers protection against these effects. New Zealand White female rabbits were assigned to five groups of six animals each: Group I, control; Group II, CsA [25 mg kg(-1) day(-1) orally (PO)]; Group III, 1% cholesterol; Group IV, 1% cholesterol + CsA (25 mg kg(-1) day(-1) PO); and Group V, 1% cholesterol + CsA (25 mg kg(-1) day(-1) PO) + TQ (10 mg kg(-1) day(-1) PO). Lipids and oxidative stress parameters [Malondialdehyde (MDA) and protein carbonyl] and aortic atherosclerosis were compared. CsA alone did not show a significant effect on either serum lipids and did not induce atherosclerosis. High-cholesterol diet induced atherosclerosis (45 ± 11% of the intimal surface of aorta was covered with atherosclerotic plaques). CsA and high-cholesterol diet increased atherosclerosis severity as measured from intimal and media lesions, but did not affect the extent of atherosclerosis. TQ decreased aortic MDA by 83%. It was also associated with reduced aortic atherosclerosis extend by 52% compared with Group IV. We concluded that (i) CsA aggravates hyperlipidemia-induced atherosclerosis and (ii) TQ attenuates the oxidative stress and atherogenesis induced by the combined effect of CsA and hyperlipidemia.