Natural beta interferon (beta IFN), derived from diploid fibroblasts, has been evaluated for its antiproliferative activity using a panel of twelve different histologic types of fresh human tumor cells. Thirty-nine percent (9/23) of the tumors showed a 70% or greater decrease in colony formation following exposure to 500 international reference units per ml of natural beta IFN, a concentration which is in the clinically achievable range. Interesting, is that leiomyosarcoma, a tumor relatively resistant to conventional chemotherapy, was uniformly sensitive (3/3) to natural beta IFN. Indeed, the antiproliferative activity of beta IFN was consistently superior (in 19/20 comparative assays) to the other conventional chemotherapeutic drugs evaluated for leiomyosarcomas. This study, which suggests that natural beta IFN exhibits significant antiproliferative activity on a variety of fresh human tumor cells, may be useful in orienting clinical trials with natural beta IFN (still in limited supply because of its unique physicochemical nature) to the more susceptible human malignancies.