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The SF-12v2 has been validated in general population and other conditions but the evidence is limited in Americans with cancer.To assess reliability and validity of SF-12v2 among adults with self-reported cancer using the Medical Expenditure Panel Survey (MEPS).Self-reported cancer participants (SCPs) were identified from 2003 MEPS. SF-12v2 was administered as part of self-administered questionnaires. Physical (PCS12) and mental (MCS12) component scores of SF-12v2 were evaluated for reliability (internal consistency, test-retest) and validity (convergent, discriminant, predictive, concurrent).420 SCPs were identified with average age of 59.3 years (SE=0.9). 10.7% had multiple cancers (>1) and 52% had at least one other chronic condition (OCC). Average PCS12 and MCS12 were 45.09 (SE=0.5) and 50.75 (SE=0.5). PCS12 and MCS12 demonstrated high internal consistency (αPCS12=0.89; αMCS12=0.88), acceptable test-retest reliability (ICCPCS12=0.82; ICCMCS12=0.73), strongly correlated with most of the expected EQ-5D domains (r=0.51–0.71), and demonstrated strong convergent validity on perceived health (r=0.61) and perceived mental health (r=0.52). PCS12 and MCS12 were able to discriminate between groups with and without physical/cognitive limitations. Only PCS12 was negatively correlated with number of OCCs.The SF-12v2 is a reliable and valid instrument to quantify health-related quality of life among adults with self-reported cancer.