Background: Biliary tract cancers (BTCs) represent the second-most common primary liver cancers. They are a heterogeneous group of tumors that include Intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder adenocarcinoma, and ampullary carcinoma. BTCs are usually diagnosed in an advanced stage and carry a poor prognosis. A better understanding of cancer biology has led to advances in targeted treatments in other cancers but remains an unmet need in BTCs. We conducted this meta-analysis to evaluate the efficacy of anti-EGFR therapy when added to the standard platinum-gemcitabine chemotherapy as first-line in patients with advanced BTCs. Methods: A review of the medical literature was conducted using online databases. Inclusion criteria consisted of English language, diagnosis of biliary tract tumors, randomized studies of first-line platinum-gemcitabine with and without anti-EGFR therapies, and studies that reported overall (OS) and progression free survival (PFS). A meta-analysis using the fixed effects and random effects models was conducted. Results: Four randomized studies with a total of 569 patients were included. Three studies were randomized phase 2 and one was randomized phase 3. Three studies used oxaliplatin and one used cisplatin in addition to gemcitabine as the standard combination. Panitumumab was used in two studies while cetuximab and erlotinib were used in one study each. The addition of anti-EGFR agent to first-line platinum-gemcitabine in advanced BTC resulted in a superior OS (HR = 0.72, 95%CI 0.61-0.85) and PFS (HR = 0.76, 95%CI 0.63-0.92). When the analysis was restricted to anti-EGFR monoclonal antibodies, their PFS benefit persisted (HR = 0.72, 95%CI 0.55-0.95), but their OS benefit failed to reach statistical significance (HR = 0.83, 95%CI 0.65-1.07). Conclusions: This is the first meta-analysis to show the addition of anti-EGFR agents to the standard first-line platinum-gemcitabine chemotherapy improves OS and PFS in advanced BTC.