To assess whether chemosensitivity in metastatic soft tissue sarcoma (STS) is influenced by the histologic grade of the tumor, the authors retrospectively analyzed tumor responses to doxorubicin-based chemotherapy in four prospective studies conducted at the Mayo Clinic, Rochester, Minnesota, between 1976 and 1984. A total of 131 patients with metastatic STS were included in these trials. All pathologic material was reviewed by one pathologist (H.M.R.) and graded according to the four-tier grading system of Broders. One hundred and sixteen patients were accepted for analysis. Objective regression rates according to grade were as follows: Grade 4, 55% (22 of 40 patients); Grade 3, 23% (7 of 31 patients); Grade 2, 19% (5 of 27 patients); and Grade 1, 0% (0 of 3 patients). Fifteen nongradable sarcomas were analyzed separately (27% [4 of 15]). In contrast to several reports suggesting that grade does not effect response, the authors found differences in response rates to be statistically significant for Grade 2 versus Grade 4 (P = 0.003) and Grade 3 versus Grade 4 (P = 0.006), but not for Grade 2 versus Grade 3 (P = 0.7). Additional comparisons adjusted for the histologic type of STS, chemotherapeutic regimen, performance status, age, and prior treatment confirmed these results. These results suggested that, in addition to being an important prognostic factor for survival in newly diagnosed STS, histologic grade may correlate with the probability of response and should be considered a stratification factor in future studies.