Background P2Y(12) inhibitors have been widely used as an alternative to aspirin in clinical practice for secondary stroke prevention. We aimed to compare the efficiency and safety of P2Y(12) inhibitors and aspirin for stroke prevention in patients with previous stroke or transient ischaemic attack (TIA). Methods PubMed, Embase, and Cochrane Central Register of Controlled Trials were searched. All randomized trials that compared P2Y(12) inhibitors with aspirin among patients with stroke were included. The primary efficacy outcomes of our meta-analysis included stroke, vascular events, and all-cause death. The primary safety outcome was minor or major bleeding events. Results The search identified 4 randomized clinical trials comparing P2Y(12) inhibitors with aspirin for secondary stroke prevention that collectively enrolled 24508 patients (12253 received P2Y(12) inhibitor and 12255 received aspirin). Pooled results from the random-effects model showed that there were no significant differences in the risk of any stroke (OR 0.90 (0.78-1.04); I-2=56.9%), vascular event (OR 0.91 (0.74-1.13); I-2=78.3%), all-cause death (OR 0.98 (0.83-1.17); I-2=0%), or minor or major bleeding (OR 1.13 (0.70-1.82); I-2=79%) among patients who received a P2Y(12) inhibitor or aspirin. P2Y(12) inhibitors were associated with a significantly lower risk of recurrent ischaemic stroke (OR 0.84 (0.73-0.96); I-2=25%) than aspirin. Conclusion This meta-analysis suggests that P2Y(12) inhibitors are more effective than aspirin in preventing recurrent ischaemic stroke among ischaemic stroke patients despite the absence of any effect on a new ischaemic or haemorrhagic stroke, a new clinical vascular event, all-cause death, and major or minor bleeding events.