Purpose: To compare women and men with dyspepsia in terms of symptoms, physical and mental well-being and the relationships between individual symptoms and well-being. Methods: A cross-sectional random telephone survey of 2300 Australians identified 748 people with dyspepsia who were interviewed regarding the number, types and severity of symptoms and physical (PCS) and mental well-being (MCS) measured by the SF-12. Results: There were no significant gender differences in number or average severity of symptoms. Bloating, nausea, and early satiety were significantly more frequent among women; food regurgitation and heartburn in men. Dyspeptics (PCS = 47.1, MCS = 46.0) had poorer physical (p < 0.001) and mental well-being (p < 0.001) than did non-dyspeptics (PCS = 53.5, MCS = 55.3). Among dyspeptics, women (PCS = 46.4, MCS = 44.7) had poorer physical (p < 0.05) and mental well-being (p < 0.001) than males (PCS = 47.9, MCS = 47.5). Some symptoms were associated with low well-being for both sexes e.g. nausea. For women retching was related to poor physical well-being, and food regurgitation, dysphagia, bloating and epigastric pain to poor mental well-being. Among men epigastric pain and heartburn were associated with poor physical well-being, acid regurgitation with poor mental well-being, and vomiting with both. Conclusions: Dyspeptics report poorer physical and mental well-being than do non-dyspeptics. The difference between groups is greater for mental well-being, especially among women. Both physical and social factors may contribute to gender differences.