Abstract: Objective To study the effects of irbesartan and perindopril combination treatment on the changes of calcineurin（CaN） ,sarcoplasmic reticulum Ca²⁺-ATPase(SR Ca²⁺-ATPase) and plasma and myocardium angiotensin Ⅱ（Ang Ⅱ） in pressure overload-induced cardiac hypertrophy in rats. Methods Forty male adult Sprague Dawley rats were divided into 5 groups: sham operation group and aortic banding groups. One week after operation, rats were gavaged with normal saline, perindopril, irbesartan or combination of perindopril and irbesartan. LVMI, plasma and tissue Ang Ⅱ, CaN and SR Ca²⁺-ATPase activity were determined at the end of 6 week treatment. Results LVMI（control:2.99±0.16 vs combination:2.14±0.12,Irbesartan:2.36±0.13,Perindopril:2.39±0.16）mg/g（P＜0.05）, CaN （control:0.61±0.03 vs sham:0.44±0.04 ,Perindopril:0.51±0.05, Irbesartan:0.51±0.03, combination:0.49±0.04）A₄₁₀nm/mg·pr（P＜0.05） activity were remarkably decreased after drug intervention which was most remarkable in the combination group. The levels of Ang Ⅱ in plasma（Irbesartan:630±50.7 vs sham:309±29.9,control:310±36.8, Perindopril:288±36.9, combination:327±46.10）pg/mL（P＜0.05） and myocardium（Irbesartan:7.15±0.50 vs sham:3.11±0.93, control:5.04±0.35, Perindopril:3.21±0.34,combination:3.31±0.36）pg/mL（P＜0.05） were remarkably increased in irbesartan group. SR Ca²⁺-ATPase activity were increased after drug intervention（control:3.6±0.69 vs sham:6.85±0.88, Perindopril:4.51±0.58, Irbesartan:4.45±0.55, combination:5.63±0.61）mmol Pi/g protein·h（P＜0.05）, especially in the combination group. LVMI was positively correlated with CaN（r=0.80, P＜0.01）, negatively correlated with SR Ca²⁺-ATPase（r=-0.726, P＜0.01）. Conclusion Irbesartan increased Ang Ⅱ in myocardium while perindopril did not. Both irbesartan and perindopril decrease CaN activity, increase SR Ca²⁺-ATPase activity. Irbesartan and perindopril combination treatment was shown to have better effects on regression of ventricular hypertrophy.