A high plasma homocysteine level is associated with early onset of coronary artery disease (CAD), particularly in homozygotes for the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene. Family history is a predictor of increased plasma homocysteine and may be involved in early-onset CAD. This study examined the relations among family history, plasma homocysteine, and age at onset of CAD, and the role of the MTHFR genotype in this context. We screened 284 patients who developed first symptoms of CAD at < or =65 years of age for fasting plasma homocysteine and the C677T mutation. On multiple regression analysis, homocysteine, family history, male gender, and smoking were independently associated with age at onset of CAD. However, separate analysis of patients who had the MTHFR 677 T/T genotype (n = 57) and those who did not (n = 209) showed that plasma homocysteine and family history were associated with earlier onset of CAD only in T/T homozygotes and that family history in patients who had this genotype was also associated with higher plasma homocysteine levels and a stronger association between plasma homocysteine and age at onset of CAD. In patients who had other genotypes, these associations were not observed, and earlier onset of CAD was associated only with male gender and smoking. Thus, the MTHFR genotype modifies the effects of family history and other risk factors on age at onset of CAD. In T/T homozygotes, family history is associated with earlier onset of CAD, higher plasma homocysteine levels, and a stronger association between plasma homocysteine and age at onset of CAD.