Background: The National Quality Forum has endorsed a minimum of 12 lymph node (LN) as a surrogate measure of quality in colorectal cancer (CRC). The prognostic value of ultrastaging hematoxylin and eosin (H&E) negative LNs (N0) using pan-cytokeratin immunohistochemistry (pan-CK-IHC) is unknown. Purpose: To assess the effect on survival of surgical quality and focused pathologic analysis. PATIENTS AND Methods: Between 2001 and 2007, 253 evaluable patients with resectable CRC were enrolled. Multiple sectioning and pan-CK-IHC were performed on N0 LNs (American Joint Commission on Cancer Stage II). Follow-up was performed at 6-month intervals with a 4-year disease-free survival (DFS) primary end-point. Results: There were 253 patients, 177 N0 and 76 N1/N2 patients, staged conventionally. Thirty-six (20%) N0 patients were upstaged using ultrastaging (N0→N0i+ [n = 27] and N0→N1mi [n = 9]). At a mean follow-up of 3.4 ± 1.6 years, 38 (15%) have recurred. Only 3% (3/108) of patients with ≥12 LNs, negative by H&E and pan-CK-IHC (N0i-), compared with 18% (6/33) with <12 LNs/N0i-(6/33; P = 0.0015) have recurred. Four-year DFS differed significantly according to surgical quality (<12 vs. ≥12 LNs) among Stage II patients only (DFS, <12 vs. ≥12 LNs: Stage I, 90.5% vs. 97.7%, P = 0.22; Stage II, 67.5% vs. 94.7%, P = 0.0036; Stage III, 61% vs. 61%, P = 0.61). Conclusion: This represents the first prospective report demonstrating that both surgical quality and nodal ultrastaging impacts survival in Stage II CRC. Patients with Stage II CRC having ≥12 LNs negative for micrometastases (N0i-) are likely cured by surgery alone. Both surgical and pathologic quality measures are imperative in early CRC to improve patient selection for adjuvant chemotherapy.