OBJECTIVE In a study of 112 cases of invasive breast cancer, the prognostic value of the gradient of nuclear volume (NV) changes was examined. STUDY DESIGN On conventional histologic slides of surgically resected specimens, we studied the nuclear changes from early to advanced. The former was represented by the noninvasive area in the tumor periphery and the latter by the invasive area with true neoplastic stroma. We analyzed the difference in NV between the noninvasive area in the tumor periphery (NVcis) and the invasive area where the nuclei are large (NVlarge), a zone we assessed to have the greatest cancer progression. Based on these measurements, we defined NV gradient index (NVG index) as the ratio of NVlarge to NVcis. RESULTS The NVG index in cases of cancer death (4.33 +/- 1.70, n = 35) was significantly larger than in relapsing survivors (2.76 +/- 1.31, n = 13, P = .002) and in relapse-free survivors (2.17 +/- 1.60, n = 64, P < .0003). In the group of cancer deaths, the correlation coefficient between NVG index and survival was -0.398 (0 < P < .02). Even in cases of stage I, NVG index in the group of cancer deaths (5.68 +/- 1.4) was significantly larger than in relapsing survivors (2.42 +/- 1.2) or relapse-free survivors (1.74 +/- 0.55). By multivariate analysis, NVG index was independently prognostic for disease-specific survival (P = .0001). CONCLUSION The NVG index contributes to discrimination between possible survivors and cancer deaths. Though there are exceptions, cases with a small NVG index can be expected to survive for a longer period even after a relapse.