To study the effect of residual microscopic resection line disease in gastric cancer, we compared 47 patients with positive margins to 572 patients who underwent R0 resections using a multivariate analysis of factors affecting outcome. Although the presence of positive margins was a significant and independent predictor of outcome for the entire group (N = 619), this factor lost significance in patients who had undergone D2 or D3 lymph node dissections (N = 466). Subset analysis within the D2/D3 group determined that this finding was limited mainly to those patients with.5 positive nodes (N = 189). The survival of patients who had </=5 positive nodes (N = 277) was significantly worsened by a microscopically involved margin. Supporting this observation, intraoperative reexcision of microscopic disease based on frozen section analysis resulted in a significant improvement in overall survival in patients with </=5 positive nodes but not in those with >5 positive nodes. We conclude that the significance of a positive microscopic margin in gastric cancer is dependent on the extent of disease. This factor is not predictive of outcome in patients who have undergone complete gross resection and have pathologically proved advanced nodal disease. Thus the goal in these cases should be an R0 resection when feasible but with the realization that the presence of >/=5 positive nodes (N2 disease according to the 1997 American Joint Committee on Cancer criteria) will mainly determine outcome and not microscopic residual cancer at the margin.