In Japan, mass screening for gastric cancer with photofluorography was initiated in 1960. At present, over 6 million people are screened annually. The sensitivity and specificity of photofluorography are 70%–90% and 80%–90%, respectively. The 5-year survival rate is 15%–30% better in screen-detected cancers than in symptom-diagnosed cases. Although no randomized controlled trials have been reported, cohort and case-control studies generally showed a decreased risk of mortality from gastric cancer in the screened subjects. The summary odds ratio (95% confidence interval) of three case-control studies for ever screened versus never screened subjects was 0.39 (0.29–0.52) for men and 0.50 (0.34–0.72) for women. Substantial evidence indicates that the Japanese screening program with photofluorography is effective in reducing the mortality from gastric cancer. The measurement of serum pepsinogens has recently drawn attention as an alternative to photofluorography, given its lower cost and simplicity. Some studies have suggested a comparable accuracy for the two methods. However, these investigations may have overestimated the relative sensitivity of serum pepsinogen testing compared with photofluorography, because serum pepsinogen testing was conducted as prevalent screening, while photofluorography was done as incident screening. Furthermore, no studies have directly examined whether the screening with serum pepsinogens reduced gastric cancer mortality. Therefore, at present, evidence is insufficient to determine the benefit of this program.