Infection with Helicobacter pylori is a major risk factor for chronic atrophic gastritis (CAG), a precursor lesion of intestinal gastric cancer. The pathogenicity of the bacterium is thought to play an important role in determining the extent and severity of clinical outcome. We aimed to assess the associations between CAG and the serostatus of antibodies to 15 H. pylori proteins. The analyses were based on 534 cases with serologically defined CAG and 1,068 age-matched and sex-matched controls participating in a population-based study conducted in Saarland, Germany among 9,953 men and women ages 50 to 74 years. A newly developed H. pylori multiplex serology method was used to detect antibodies specific to 15 H. pylori antigens. Significant associations were observed between seropositivity for all 15 specific antibodies and the presence of CAG. Exclusion of severe cases, who might have lost the infection in the course of CAG progression, substantially increased the observed associations. In H. pylori-seropositive subjects, cytotoxin-associated gene A (CagA), vacuolating toxin (VacA), helicobacter cysteine-rich protein C (HcpC), and the chaperonin GroEL were identified as independent virulence factors for CAG with adjusted odds ratios (95% confidence interval) of 3.52 (2.01-6.10), 3.19 (1.44-7.05), 4.03 (1.53-10.65), and 2.65 (1.06-6.62), respectively; the simultaneous presence of all four independent virulence factors was associated with an 18-fold risk of CAG. In conclusion, HcpC and GroEL were identified as new independent virulence factors, and in combination with the established virulence factors, CagA and VacA, were strongly associated with CAG.