Background: Early diagnosis of patients with upper gastrointestinal cancer is important because many cases are diagnosed in advanced stages and have poor prognosis. Several studies have reported increased serum levels of hyaluronic acid and laminin in various cancers and the correlation of the levels with poor prognosis. However, little data on the use of serum hyaluronic acid and laminin levels for early detection of esophageal and gastric cancers are available. Methods: We assessed serum hyaluronic acid and laminin levels using enzyme-linked immunosorbent assay in 20 gastric cardia cancer, 23 gastric noncardia cancer and 20 esophageal squamous cell carcinoma incident cases and 25 controls in the Golestan Province, northern Iran, a high risk area for upper gastrointestinal cancers. Results: Mean serum hyaluronic acid and laminin concentrations in cancer cases were higher than in controls in crude analyses. Significant correlations were observed between hyaluronic acid levels and gastric noncardia cancer (Beta-coefficient = 0.390; P = 0.01) and esophageal squamous cell carcinoma (Beta-coefficient = 0.332; P = 0.05) and between laminin levels and gastric cardia cancer (Beta-coefficient = 0.454; P = 0.003) in multivariate models. For esophageal squamous cell carcinoma, gastric cardia cancer, and gastric noncardia cancer, area under ROC curve (AUC) of hyaluronic acid was 0.708, 0.694, and 0.770, and of laminin was 0.706, 0.828, and 0.671. Conclusions: Our study suggests that hyaluronic acid and laminin may be used to identify potentially high-risk groups of upper gastrointestinal cancers for further diagnostic work-ups, particularly in high incidence areas. Nevertheless, further studies with larger sample size and tumor staging information are warranted to clarify the clinical significance of hyaluronic acid and laminin in those cancers. © 2011 European Federation of Internal Medicine.