Serum carbohydrate antigen 19-9 (CA 19-9) has been identified as biochemical marker for biliary tract cancer (BTC). The purpose of this study was to evaluate its value as a treatment response marker and its value as a prognostic parameter in patients with unresectable BTC. We analyzed 70 patients with BTC treated with chemotherapy. CA 19-9 levels before and after two treatment courses were analyzed with respect to their effect on treatment response. Patients were categorized into two subgroups according to biliary stenting: patients without endoscopic intervention or biliary drainage (non-stent subgroup) and patients with endoluminal stenting (stent subgroup). Pretreatment CA 19-9 levels were prognostic with respect to overall survival for the entire study population. Patients with CA 19-9 levels above the median of 300 units/mL had a nearly 3-fold risk for early death (hazard ratio, 2.92; 95% confidence interval, 1.51-5.64; adjusted P = 0.002) as compared with patients with CA 19-9 levels <or=300 units/mL. An association between CA 19-9 and therapeutic response was observed in the non-stent subgroup (P = 0.001) only. Furthermore, the decrease of CA 19-9 levels after treatment was predictive for improved survival in the non-stent subgroup (adjusted P = 0.018) but not in the stent subgroup. Our results indicate that pretreatment CA 19-9 levels and CA 19-9 decrease after chemotherapy are of prognostic relevance in patients with BTC.