PURPOSE: We assessed the benefit of adjuvant aspirin in resected PIK3CA-mutated colon cancer patients. PATIENTS & METHODS: This was a phase III, prospective, randomized, placebo-controlled, double-blind, multicenter, and multinational trial. Patients with resected colon cancer stage II and III harbouring an activating PIK3CA mutation were included. Due to financial constraints, the trial was prematurely closed. Randomization was 2:1 to aspirin 100mg versus placebo daily for 3 years. The primary endpoint was disease-free survival (DFS). Secondary endpoints included the time to disease recurrence (TTR), overall survival, and adverse events (AE). RESULTS: Overall, 1,040 patients were screened for PIK3CA mutations, with 112 randomized to aspirin (N=74) and placebo (N=38). Median age was 66 years and 42.9% were female. After a median follow-up of 4 years, 19 DFS events occurred, including 10 in the aspirin and nine in the placebo arm. The HR for DFS was 0.57 (90%CI: 0.27-1.22), in favor of aspirin (p=0.11). DFS rates at 5 years were 86.5% (90%CI: 77.7%-92.0%) in the aspirin and 72.9% (90%CI: 55.7%-84.3%) in the placebo arm. The HR for TTR was 0.49 (90%CI: 0.21-1.19, p=0.089) in favor of aspirin. No patient experienced aspirin-related serious AEs. CONCLUSIONS: The SAKK 41/13 is the first randomized trial to provide clinical evidence of a protective effect of adjuvant aspirin in resected PIK3CA-mutant colon cancer patients, with clinically relevant DFS and TTR improvements. Although results were not statistically significant due to premature study closure, adjuvant aspirin warrants individual consideration in patients with resected PIK3CA-mutant colon cancer stage II and III.