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The strategy of discarding diminutive colonic polyps (≤5 mm) has been discussed for many years. However, despite their exceedingly low risk of malignancy, implementation has remained limited, with minimal impact on clinical practice. More recently, computer-assisted optical diagnosis (CADx) has been introduced to support and potentially enable broader adoption of this approach. We prospectively assessed patient acceptance and examiner-based quality control in 95 out of 102 patients (93.1%) who consented to this approach, involving a total of 149 polyps. Of these, 143 polyps were reviewed by three examiners blinded to CADx diagnoses and the results were compared with CADx diagnoses. Resect-and-discard accuracy was 83.5% excluding sessile serrated lesions (SSLs), while treating SSLs as neoplastic or hyperplastic yielded 75.9% and 84.3%, respectively. Excluding SSLs, the diagnose-and-leave negative predictive value was 92.3%. Surveillance interval recommendations based on CADx and expert review, aligned with current guidelines, achieved 100% concordance, ensuring appropriate follow-up.