Introduction The incidence of gastric cancer (GC) arising in the upper third of the stomach, including the cardia or gastroesophageal junction (GEJ), has increased in the last decades due to established etiological risk factors such as diet, obesity, and gastroesophageal reflux. We conducted a systematic review and meta-analysis to determine the prognostic role of site of origin in patients with proximal versus distal GC. Material and Methods We conducted a search of the PubMed, Cochrane Library, SCOPUS, Web of Science, EMBASE, Google Scholar, LILACS, and CINAHL databases from inception to September 2016. Studies reporting data on the independent prognostic effect of site in GC and comparing overall survival (OS) in proximal versus distal tumors were eligible. Data were pooled using OS hazard ratios (HRs) of proximal versus distal GC according to fixed- or random-effect model. Results Overall, 50 studies including 128,268 patients were identified. Cancers located in the upper third of the stomach were associated with a significantly increased risk of all-cause mortality (HR 1.31, 95% confidence interval CI 1.17–1.46, p  < 0.001, I 2  = 91%). After exclusion of GEJ tumors, prognosis was worse for pure cardia location (HR 1.39, 95% CI 1.22–1.58, p  < 0.001, I 2  = 61%) compared with proximal or upper-third GCs without a specific subsite definition (HR 1.18, 95% CI 1.01–1.37, p   =  0.04, I 2  = 91%). Conclusions Location of the primary GC in the upper third of the stomach, particularly at the GEJ/cardia, should be acknowledged as an important prognostic factor. Based on these results, more effective treatment strategies for proximal GCs are needed.