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Abstract: Introduction: Despite recent meta-analyses suggesting that homocysteine is an independent predictor of coronary heart disease (CHD), there is debate regarding whether elevated homocysteine may be deleterious only in the presence of other risk factors, with which it acts synergistically to exert a multiplicative effect on CHD risk, emerging only as a CHD predictor in patients with pre-existing risk factors. The Prospective Epidemiological Study of Myocardial Infarction (PRIME) Study is a multicentre prospective study of 10593 men from France and Northern Ireland, investigating cardiovascular risk factors. We investigated: (1) whether higher homocysteine is associated with increased CHD risk in the PRIME case-control cohort; (2) whether homocysteine interacts synergistically with pre-existing CHD risk factors. Methods: Homocysteine was measured in 323 participants who had developed CHD at 5-year follow-up and in 638 matched controls. Results: There was no significant difference in homocysteine between cases and controls (p =0.18). Homocysteine was significantly higher in current smokers (geometric mean μmol/l (interquartile range μmol/l) 9.45 (7.43, 11.75)) compared with non-smokers (8.90 (7.32, 10.70); p =0.007). There was a significant interaction between homocysteine, smoking and CHD risk (χ 2 =10.29, d.f.=2, p =0.006). Conclusions: These findings suggest that elevated homocysteine is significantly associated with CHD risk in current smokers. [Copyright &y& Elsevier]