Background: In patients (pts) with biliary tract cancer (BTC), relapse occurs at a high frequency even after curative resection. It remains unclear whether in pts with postoperative recurrence receiving chemotherapy, the surgery exerts any influence on the risk of development of toxicities. The aim of this study was to compare the outcomes and incidences of adverse events between recurrent BTC (rBTC) pts and unresectable BTC (uBTC) pts receiving gemcitabine plus cisplatin chemotherapy (GC). Methods: Data of pts with rBTC or uBTC receiving GC as the first-line chemotherapy were analyzed. The GC regimen consisted of gemcitabine 1000 mg/m² plus cisplatin 25 mg/m²on days 1 and 8, administered every 3 weeks. All adverse events occurring during the first 180 days of GC were evaluated according to CTCAE, version 4.0. Results: A total of 151 pts, including 55 pts with rBTC and 96 pts with uBTC, were enrolled. In regard to the baseline characteristics, no significant differences between the rBTC and uBTC groups were found in the gender distribution [male: 69% vs. 57%], age [median: 68 vs. 68], or ECOG performance status (PS) [PS0: 67%vs. 55%]. The distribution of the primary tumor site (intrahepatic bile duct [27% vs. 33%] / extrahepatic bile duct [45% vs. 20%] / gallbladder [20% vs. 44%] / ampulla [7% vs. 3%]) was unbalanced between the two groups (p< 0.01). The overall survival (OS) was significantly longer in the rBTC group than that in the uBTC group [median 15.8 months vs. 10.0 months, p = 0.02], however, there was no significant difference in the progression-free survival [median 6.8 months vs. 5.8 months] between the two groups. Grade 3-4 neutropenia was more frequent in the rBTC group [69%] as compared to that in the uBTC group [44%, p< 0.01], whereas Grade 3-4 cholangitis was significantly less frequent in the rBTC [5%] group than that in the uBTC group [21%, p = 0.02]. Conclusions: The incidence of Grade 3-4 neutropenia developing during GC was significantly higher in the rBTC group as compared to that in the uBTC group.