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Sex-specific evidence on de-escalation strategies of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention in patients with acute coronary syndromes (ACS) remains limited. Females are often under-represented in randomized controlled trials (RCTs) and sex-based subgroup analysis in RCTs yield conflicting results. We searched PubMed and EMBASE in September 2024 for RCTs that investigated DAPT strategies for patients with ACS. We examined whether there are differences in the efficacy and safety of de-escalation strategies (i.e., short-term DAPT (≤6 months), unguided de-escalation, and guided de-escalation with genotype or platelet function tests) compared to standard DAPT (12 months) between sexes. A systematic review and meta-analysis were performed to compare the efficacy and safety between sexes with p-value for test of moderators. The primary efficacy outcome was major adverse cardiovascular events (MACEs), defined as a composite of cardiovascular death, myocardial infarction, and stroke. The primary safety outcome was major or minor bleeding. Fourteen RCTs involving 35,901 patients with ACS (7,652 female patients, 28,249 male patients) were included. The effect of de-escalation strategies on the primary efficacy outcome was significantly different between female (HR, 0.74; 95% CI, 0.57-0.95; I²=0%) and male patients (HR, 1.04; 95% CI, 0.90-1.19; I²=15%), with p-value for test of moderators 0.019. The primary safety outcome showed no significant sex differences (p-value for test of moderators=0.67). In conclusions, in patients with ACS, compared to standard DAPT, de-escalation strategies were more effective in reducing MACE in female than in their male counterparts. Meanwhile, de-escalation strategies were similarly safer for both sexes.