Background: Cholangiocarcinoma (CCA)management is constantly being updated in view of existing evidence in order to establish practice guidelines and consensus statements. Here, we evaluate and compare the potential efficacy of chemotherapy combination of Gemcitabine plus Cisplatin versus non- Gemcitabine and Cisplatin regimens as a neo-adjuvant treatment for cholangiocarcinoma patients prior to liver transplantation. Methods: In this prospective study, patients with locally advanced, unresectable, hilar, or intrahepatic CCA with no evidence of extrahepatic disease or vascular involvement were treated with either the combination of neo-adjuvant Gemcitabine plus Cisplatin with no radiation or other standard options of neo-adjuvant treatment. All patients included received chemotherapy prior to being listed for liver transplantation at a single cancer center in collaboration with the same institution’s transplant center according to an open-labeled, and centers-approved clinical management protocol. Patients were listed for liver transplantation if they had a minimum of six months of scans showing response or confirmation of disease stability. This report, which was censored on November 30, 2021, was an initial prospective study of patients treated under this ongoing clinical treatment protocol. Results: Out of a total of 707 liver transplant recipients, 37 patients were confirmed with a diagnosis of CCA and only 18 patients (11 males and 7 females) with a median age of 61.83 [interquartile range (IQR): 58.27-68.74] met inclusion criteria. Of the 18 patients enrolled, 10 received Gemcitabine/Cisplatin, while 8 patients received either Gemcitabine monotherapy or Capecitabine or FOLFIRI alone or with Cetuximab. Days for recurrence after transplantation was 603 (IRQ: 603-603) in the Gemcitabine/Cisplatin group and 285 (267-374) days in the non-Gemcitabine/ Cisplatin group (p-value = 0.18). The median days of follow-up in the Gemcitabine/Cisplatin group were 753 (621-885) days versus 1050 (618-1489) days in the non-Gemcitabine/ Cisplatin group (p-value = 0.25). In the non-Gemcitabine/ Cisplatin group, overall survival was 75% (95% CI 31-93%) at both years 1 and 2; 63% (95% CI 23-86%) at both years 3 and 4. In the Gemcitabine/ Cisplatin group, overall survival was 100% (95% CI 100-100%) at both years 1 and 2; 67% (95% CI 5-95%) at both years 3 and 4. Three patients in the non-Gemcitabine/ Cisplatin group died at 328 days, 340 days, and 896 days, respectively. One patient in the Gemcitabine/ Cisplatin group died at 885 days. Conclusions: To our knowledge, this is the first report to show improved overall survival outcomes with Gemcitabine plus Cisplatin as neo-adjuvant treatment with no concomitant radiation compared to non-Gemcitabine/ Cisplatin regimens in patients with CCA prior to liver transplantation.