BACKGROUND AND AIMS: Current guidelines recommend endoscopy for dyspeptic patients >45 yr of age and/or with "alarm" symptoms. The management of younger patients with uncomplicated dyspepsia is controversial. The objective of the study was to identify any risk factors predictive of upper gastrointestinal malignancy in patients with uncomplicated dyspepsia and validate their ability in refining indications for endoscopy. METHODS: Prospective database study of consecutive uninvestigated dyspeptic outpatients undergoing endoscopy was performed. A questionnaire including multiple possible prognostic variables was systematically submitted to patients prior to endoscopic examination. Risk factors for upper gastrointestinal malignancy identified were used to derive a prediction rule subsequently validated on an independent population. RESULTS: A total of 5,224 patients with uncomplicated dyspepsia were considered (training sample). Twenty-two (16 males) had malignancy at endoscopy. These patients were about 20 yr older than patients with no malignancy (p < 0.001). The mean age of females with cancer was almost 10 yr higher compared to males (p= 0.08). Such differences in age were confirmed in a split sample of 3,684 patients (p < 0.001 and p < 0.05, respectively). The age cut-offs identified were 35 yr for males and 56 yr for females. CONCLUSIONS: The age threshold for endoscopy should be lowered in males to decrease the risk of missing cancers, and can be safely increased in females without affecting outcomes. In patients with uncomplicated dyspepsia, the combination of age and gender provides a better discriminant power than age alone.