From January 1978 to December 1980, 222 patients with metastatic breast cancer were included into a prospective multicenter trial. All patients were treated once a month with six cycles of VAC- (vincristine, adriamycin, cyclophosphamide) chemotherapy, followed by FMC (5-fluorouracil, methotrexate, cyclophosphamide) until progression was documented. By random assignment, the patients received immunostimulation with Corynebacterium parvum (CP) by one of four methods: subcutaneous (SC) on either day 1 or day 14, intravenous (IV) on either day 1 or day 14. The 214 evaluable patients were equally distributed to the four arms. The rates of complete or partial response to VAC/FMC plus CP did not differ significantly between the treatment groups. Of our patients, 22-33% were definite treatment failures. The Kaplan-Meier curves of duration of remission (medians 14 vs. 9 vs. 13 vs. 11 months) did not differ significantly. Only small differences in survival were noted among the four study groups (medians 15.4 vs. 17.5 vs. 17.2 vs. 13.0 months). However, complete and partial responders lived significantly longer (Log rank test P = 0.008), when CP was given on day 14 by the SC rather than IV route (29+ vs. 14.3 months). Patients in the four study groups were treated with virtually identical doses of VAC/FMC chemotherapy. Patients receiving CP intravenously on day 14 experienced significantly lower mean leukocyte counts than patients in the other groups. Many patients suffered from high temperature (requiring treatment with antipyretics) and severe gastrointestinal toxicity, particularly when CP was given IV on day 1 together with the chemotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)