Health-related quality of life (HRQL) has become an important outcome measurement in hematology. Our aim was to validate the quality of life questionnaire (QLQ)-MY20 instrument in patients with multiple myeloma (MM) in Mexico. The Mexican-Spanish versions of the QLQ-C30 and QLQ-MY20 instruments were applied to patients with MM at a cancer referral centre. Reliability and validity tests were performed. Test-retest was carried out in selected patients. Ninety-eight patients with MM were included in this study. Questionnaire compliance rates were high, and the instrument was well accepted; internal consistency tests demonstrated good convergent and divergent validity. Cronbach's α coefficients of seven of nine multi-item scales of the QLQ-C30 and of all three multi-item scales of the QLQ-MY20 instruments were >0.7 (range, 0.36-0.89). The scales of the QLQ-C30 and QLQ-MY20 instruments distinguished among clinically distinct groups of patients; 9 of 15 scales of the QLQ-C30 and all 4 scales of the QLQ-MY20 presented responsiveness after change over time. The Mexican-Spanish version of the QLQ-MY20 questionnaire is reliable and valid for the assessment of HRQL in patients with MM and can be used in clinical trials in the Mexican community.