BACKGROUND Metastatic small bowel adenocarcinoma (SBA) has a poor prognosis. Because of the rarity of SBA, only a few studies have evaluated the role of chemotherapy in the treatment of metastatic SBA; thus, the benefit, if any, of adding a platinum compound to fluorouracil (5-FU) is unknown. The objective of this retrospective study was to determine whether the addition of a platinum compound to 5-FU provided any benefit in the treatment of patients with metastatic SBA. METHODS The authors identified 80 patients with metastatic SBA who were treated with chemotherapy at the University of Texas M. D. Anderson Cancer Center between 1978 and 2005. Response rates, progression-free survival (PFS), and overall survival (OS) were compared between patients who received 5-FU and a platinum compound and patients who received other chemotherapy combinations. RESULTS The median patient age was 53 years. The primary tumor site was the jejunum in 35 patients (43%), duodenum in 30 patients (38%), ileum in 6 patients (8%), and nonspecified small bowel in 9 patients (11%). Of all 80 patients, 29 patients (36%) received 5-FU and a platinum compound, 41 patients (51%) received 5-FU without a platinum compound, and 10 patients (13%) received non-5-FU-based treatment. Compared with other chemotherapy regimens, treatment with 5-FU and a platinum agent resulted in a higher response rate (46% vs 16% with other regimens; P = .01) and longer median PFS (8.7 months vs 3.9 months; P < or = .01) but not better OS (14.8 months vs 12 months; P = .1). In multivariate analysis, treatment with 5-FU and a platinum compound was a significant predictor of response (odds ratio, 4.5; 95% confidence interval [CI], 1.3-15.8; P = .02) and PFS (hazard ratio. 0.49; 95% CI, 0.29-0.84; P = .01) but only reached borderline significance for OS (hazard ratio, 0.63; 95% CI, 0.37-1.07; P = .08). CONCLUSIONS To the authors' knowledge, the current analysis represents the largest number of patients with metastatic SBA treated with chemotherapy in the literature, and the results suggested that the combination of 5-FU and a platinum compound leads to a higher response rate and PFS compared with other chemotherapy regimes. The authors concluded that prospective investigation of platinum analogues in the treatment of SBA is warranted.