Health-related quality of life (HRQL) is a fundamental outcome in surgical oncology and culturally valid tools are essential for this purpose. Our aim was to validate the Mexican-Spanish versions of the European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire QLQ-C30 and the QLQ-STO22 disease-specific questionnaire module in Mexican patients with gastric cancer (GC). The translation procedure followed EORTC guidelines. Both instruments were completed by patients with GC and analyses were performed within three clinically distinct groups: (1) patients undergoing palliative treatment, (2) patients undergoing treatment with curative intent, and (3) GC survivors. Tests for reliability and validity were performed. One hundred and fifty patients (mean age 54.2 years) completed both questionnaires. Sixty-seven, 55, and 28 patients were allocated to groups 1, 2, and 3, respectively. Compliance rates were high, and questionnaires were well-accepted. Survivors of treatment for GC reported better functional HRQL scores and lower symptom scores than patients in group 2 who were currently undergoing treatment. Patients selected for potentially curative treatment had better HRQL than group 1 (palliative treatments). Scales in the QLQ-C30 and QLQ-STO22 distinguished between other clinically distinct groups of patients. Cronbach's α coefficients of 14 scales of both questionnaires were >0.7. Multitrait scaling analysis demonstrated good convergent and discriminant validity. Test-retest scores were consistent. We conclude that the Mexican-Spanish versions of EORTC QLQ-C30 and QLQ-C22 questionnaires are reliable and valid for HRQL measurement in patients with GC and are therefore recommended for use in clinical trials of Mexican community.