The laminin-5 gamma 2 chain (LN-5gamma2) is known to be a marker of invasion in several cancer types. Our purpose was to examine the prognostic significance of LN-5gamma2 expression in different areas of individual colorectal cancers (CRCs) by using tissue microarrays (TMAs), and to clarify the optimal areas for prognostic assessment. Using formalin-fixed paraffin-embedded tissue blocks of pT3 primary CRCs resected from 120 patients, we constructed TMA blocks of tissue core specimens taken from the submucosal invasive front, subserosal invasive front, central area, and rolled edge of each tumor. Using these four-point TMA sets, cytoplasmic LN-5gamma2 expression was immunohistochemically surveyed, and the area-specific prognostic significance of LN-5gamma2 expression was evaluated. The data revealed that 35, 30, 15 and 10% of the 120 CRCs showed high-grade LN-5gamma2 expression in the submucosal invasive front, subserosal invasive front, central area and rolled edge, respectively. Disease-specific survival curves for the groups with high- and low-grade LN-5gamma2 in the submucosal invasive front and subserosal invasive front were different significantly or of marginal difference (respective 5-year survival rates: 54 and 78% for submucosal invasive front (P=0.030) and 58 and 75% for subserosal invasive front (P=0.055)). Multivariate analysis revealed that the grades of LN-5gamma2 expression in submucosal invasive front (hazard ratio=2.0, P=0.047) and subserosal invasive front (hazard ratio=2.9, P=0.0033) were independent prognostic factors. In contrast, the grades of LN-5gamma2 expression in the central area and rolled edge did not have a significant impact on patient prognosis. Analysis using area-specific four-point TMAs clearly demonstrated that LN-5gamma2 expression in the invasive front largely influences the degree of clinical aggressiveness of CRC and its tendency to metastasize.