Objective To compare the effects of different degree of sedation on acute coronary syndrome (ACS) patients with mechanical ventilation. Methods Fifty-six patients with ACS who received mechanical ventilation were randomly divided into mild sedation group (group M, RASS score 0 to -2, n = 29) and deep sedation group (group D, RASS score-3 to -4, n = 27). Analgesia was achieved with Dezocine. Sedation was achieved with Dexmedetomidine and Propofol. The dose of sedation was determined based on Richmond agitation-sedation scale. Dynamic electrocardiogram continuous monitoring for 48 h was performed. Cardiovascular events including arrhythmia, acute myocardial ischemia, time duration of mechanical ventilation, ICU stay, delirium, and 28 days survival rate were compared and analyzed. Results Incidence of arrhythmia such as frequent ventricular premature beat, ventricular tachycardia, supraventricular tachyarrhythmia, and acute myocardial ischemia were decreased significantly in group D when compared with group M (P < 0.05) There was no significant difference in mechanical ventilation time , ICU length of hospital stay ,delirium and 28 days survival rate between two groups (P > 0.05). Conclusion In ACS patients with mechanical ventilation, early deep sedation can reduce the incidence of arrhythmia and acute myocardial ischemia without increase of mechanical ventilation time and ICU stay.