Recurrent or metastatic uterine sarcoma represents an ominous and aggressive form of malignant disease. In an attempt to define a beneficial treatment program, we compared treatment with doxorubicin (A) 60 mg/m2 versus a combination of doxorubicin 60 mg/m2 and cyclophosphamide 500 mg/m (CA), each regimen given every 3 weeks. Of 132 patients entered on study, 104 were eligible; 50 received A and 54 CA. Pretreatment characteristics were similar, and no patient had received prior chemotherapy. The proportion of complete responses (CR) + partial responses (PR) for measurable disease patients was 5 of 26 (19%) for both A and CA. Multivariate analysis done on progression-free interval (PFI) and survival (S) showed CA to be of no benefit over A (PFI, P = 0.22; S, P = 0.55). For both A and CA patients, measurable disease (PFI, P = 0.002; S, P = 0.02, respectively), performance status (PFI, P = 0.004; S, P = 0.0002; respectively), and sites of residual disease (PFI, P = 0.008; S, P = 0.003, respectively) were detected as prognostic variables. Conversely, histologic type, age, and recurrence status (primary versus recurrent at entry) were not prognostic indicators. These data indicate no significant benefit of CA versus A alone in patients with uterine sarcoma.