All 24 cases of confirmed and evaluable Stage I favorable histology (FH) Wilms' tumor (WT) relapsing to date on the Third National Wilms' Tumor Study (NWTS-3) were compared with 48 matched control subjects who had not relapsed for at least 2 years after diagnosis. Fifteen of the clinical and pathological variables studied, including patient age and tumor size, had no significant relationship to the outcome of this study. Four histologic features, all related to the degree of tumor extension within the "tumor-kidney unit" proved to be significantly associated with relapse. These were (1) invasion of the tumor capsule, (2) presence of an "inflammatory pseudocapsule," (3) renal sinus invasion, and (4) tumor in intrarenal vessels. One or more of these features was present in 100% of relapsed cases (excluding one for which two variables were unevaluable), but occurred in only 46% of controls (P less than 0.0002). Therefore, no relapses occurred in the NWTS-3 when all four variables were negative. This result was confirmed by a review of all Stage I cases in the NWTS-1 who had relapsed and who were treated by single-agent chemotherapy. Again, no relapses occurred when all four factors were negative. These results demonstrate the feasibility of "microsubstaging" and could serve as a basis for future refinements of therapy for Stage I favorable histology Wilms' tumor.