BACKGROUND: Patients with cardiovascular (CV) diseases are increasingly frail but rarely represented in trials. Understanding effect modification by frailty on CV trials is critical as it could help define treatment strategies in frail patients. OBJECTIVES: This meta-analysis aims to assess the implications of frailty on CV outcomes in clinical trials. METHODS: Randomized controlled trials examining the effects of frailty in the context of CV trials were included (CRD42024528279). Outcomes included a composite of major adverse cardiac events (MACE), all-cause mortality, CV mortality, hospitalizations, and frailty-specific outcomes (physical, quality of life, and frailty scores). HRs and 95% CIs were pooled for clinical endpoints, and standardized mean differences (SMDs) were calculated for frailty-specific outcomes. RESULTS: Thirty unique randomized controlled trials were included with a pooled total of 87,711 participants. Frail patients had a significantly increased risk of MACE (HR: 2.33 [95% CI: 1.87-2.91], P < 0.001, I = 83%), all-cause mortality (HR: 2.34 [95% CI: 1.80-3.05], P < 0.01, I = 75%), CV mortality (HR: 1.76 [95% CI: 1.60-1.93], P < 0.001, I = 0%), and hospitalizations (HR: 2.38 [95% CI: 1.65-3.43], P < 0.001, I = 92%) compared to nonfrail patients. In the frailest group, trial interventions decreased MACE (HR: 0.81 [95% CI: 0.74-0.88], P < 0.001, I = 0%) and hospitalization (HR: 0.81 [95% CI: 0.72-0.90], P < 0.001, I = 0%) risks with no significant difference in mortality risk (P > 0.05) compared with the control group. Trial interventions significantly improved physical (SMD: 0.15, 0.04-0.26) and quality of life (SMD: 0.15, 0.09-0.21) but not frailty scores (P > 0.05). CONCLUSIONS: While frailty prognosticated a higher risk of CV events and mortality, frailty did not reduce treatment efficacy. CV trial interventions appear beneficial even in the frailest group.