Aim To investigate the effect of captopril on endothelin (ET) and angiotensin Ⅱ (AngⅡ) and their relationship to proto oncogene in atherosclerotic rabbits. Methods 53 male Japan white rabbits were assigned randomly to the control group, cholesterol food (CF) group and high dose (HD ), middle dose (MD ), low dose (LD ) captopril plus cholesterol food group(Cap group), which were fed for 12 weeks. Levels of ET and AngⅡ were determinated by radioimmunoassay and expression of proto oncogene c myc and c fos mRNA were observed by in situ reverse transcription PCR (ISRT PCR) technique. Results (1) Levels of ET and AngⅡ were significantly increased in CF group; There were positive significantly correlation between the change of ET and AngⅡ in different experiment stage. Levels of ET and AngⅡ were significantly decreased in HD Cap group. (2) Positive sign of pro oncogene c myc and c fos mRNA are remarkably increased in proliferated intima, positive sign of pro oncogene c myc and c fos mRNA are remarkably decreased in HD Cap group. (3)There were positive significantly correlation between the change of ET and expression of proto oncogene c myc or c fos mRNA (r=0.9263, p<0.01; r=0.8541, p<0.01). Conclusion The level of ET varied closely with change of AngⅡ and expression of proto oncogene c myc and c fos mRNA. Furthermore, only captopril of high dose may have therapeutic applications to prevent atherosclerotic development effectively.