Abdominal obesity and increasing body mass index are risk factors for esophageal adenocarcinoma and its main precursor, Barrett’s esophagus; however, there are no known biological mechanisms for these associations or regarding why only some patients with gastroesophageal reflux disease develop Barrett’s esophagus. We evaluated the association between Barrett’s esophagus and multimers of an adipose-associated hormone, adiponectin. We conducted a case-control study evaluating the associations between adiponectin (total, high-molecular-weight, and low-/medium-molecular-weight) and Barrett’s esophagus within the Kaiser Permanente Northern California population. Patients with a new diagnosis of Barrett’s esophagus (cases) were matched to patients with gastroesophageal reflux disease (GERD) without Barrett’s esophagus and to population controls. Complete serologic and epidemiologic data were available for 284 cases, 294 GERD controls, and 285 population controls. Increasing adiponectin levels were a risk factor for Barrett’s esophagus among patients with GERD (total adiponectin fourth vs first quartile odds ratio [OR], 1.96; 95% confidence interval [CI], 1.17-3.27; high-molecular-weight adiponectin OR, 1.65; 95% CI, 1.00-2.73; low-/medium-molecular-weight adiponectin OR, 2.18; 95% CI, 1.33-3.56), but not compared with population controls. The associations were significantly stronger among patients reporting frequent GERD symptoms and among smokers (P values interaction < .01). Adiponectin levels are associated positively with the risk of Barrett's esophagus among patients with GERD and among smokers, but not among population controls without GERD symptoms. Higher adiponectin concentrations either independently may contribute to the aberrant healing of esophageal injury into Barrett's esophagus or be a marker for other factors.