Since the publication of several randomized trials and a meta-analysis indicating that lowering homocysteine levels with B vitamins (to reduce the effects of homocysteine on the vascular endothelium) did not result in cardiovascular benefit, the use of vitamin therapy to lower homocysteine levels is widely regarded as ineffective. However, there has been renewed interest in the issue because an analysis of studies from the National Health and Nutrition Examination Survey and the Multi-Ethnic Study of Atherosclerosis showed that adding total homocysteine level to a Framingham risk score was associated with an approximately 20% net reclassification of intermediate-risk patients.1 A recent meta-analysis raised the question of whether population folate intake and polymorphisms of methylenetetrahydrofolate reductase may alter interpretation of these clinical trials; mendelian randomization analysis suggested that the polymorphisms might be important only among individuals with low folate status. A commentary2 about that article noted the hazards of the “spinal reflex” that leads to “automatic rejection of observational data when they appear to be discrepant from trials.” A similar spinal reflex, automatic rejection of subgroup analyses, is another hazard of interpretation of clinical trials.