The purpose of this report is to evaluate toxicity, response, and survival of the cyclophosphamide-doxorubicin-cisplatin (CAP) chemotherapy regimen in patients with adenocarcinoma of unknown primary site (ACUP). Twenty-two patients with ACUP were eligible for this study between June 1992 and April 1999. There were 13 men (59%) and 9 women (41%) with a median age of 53.5 years (range: 29--78 years). Lung (seven), liver (six), vertebral bone site (six), and abdominal nodes (six) were the most common metastatic sites. Treatment consisted of doxorubicin 50 mg/m(2), cyclophosphamide 1,000 mg/m(2), and cisplatin 100 mg/m(2) (CAP), administered every 3 weeks; a total of six courses were planned. Twenty-two patients were assessable for toxicity and 20 patients were assessable for response. Grade III to IV neutropenia was observed in 14 patients (64%); febrile neutropenia occurred in 6 patients (27%) and in 10 cycles (12.5%). Grade III to IV anemia and thrombocytopenia were found in 12 (54.5%) and 9 patients (41%), respectively. Grade III to IV nausea and vomiting was observed in 9 patients (41%). Ten patients, 50% of the assessable population, obtained an objective response, including 3 complete (15%) and 7 partial (35%) responses. The median response duration was 3.9 months (range: 0.5--13.3 months). One patient (5%) had stable disease and 5 patients (25%) had progressive disease. The median overall survival and the median time to progression were 10.7 months (range: 0.4--56.9 months) and 8.8 months (range: 6.6--16.5 months), respectively. The CAP regimen in patients with ACUP had significant activity. This chemotherapy regimen induced a high level of grade III to IV toxicities and could not be considered as a treatment of reference. However, the emergence of long-term survivors among responder patients highlighted the need to search for an active treatment for patients with ACUP.