Objective: To prospectively examine the association between non-steroidal anti-inflammatory drugs (NSAIDs) use (including dose and dosage schedule) and the recurrence of colorectal adenomas among individuals who were diagnosed with an adenoma at entry into a clinical trial. Methods: For this analysis, participants who completed the full follow-up (n = 1905) for the Polyp Prevention Trial (PPT) were evaluated. Information on current use and dose of NSAIDs and other drugs was obtained at baseline and at each subsequent study visit over the duration of the trial. The study endpoint was the recurrence of colorectal adenomas in the 3 years between the 1-year trial colonoscopy (T1) and the end of the trial colonoscopy (T4). Results: There was a significant reduction in overall adenoma recurrence among NSAIDs users (odds ratio [OR] = 0.77; 95% confidence interval [CI]: 0.63–0.95), with the greatest effect seen in advanced polyps (OR = 0.51; CI: 0.33–0.79). Among aspirin users, we observed a significant dose response for overall adenoma recurrence, with a 40% reduction in the OR association (OR = 0.56; 95% CI: 0.31–0.99) among those taking more than 325 mg per day. Conclusion: This prospective study provides further evidence that NSAIDs may play an important role in the chemoprevention of recurrent colorectal adenomas, even those with advanced features.