Atheroma formation, plaque rupture and thrombosis represent the pathophysiological processes underlying the development of acute coronary syndromes (ACS). Evidence indicates a fundamental role of inflammatory processes in all stages of development of ACS. Aim. The aim of this study was to determine the associations of plasma complement C3 and C-reactive protein with MI in a case-control study. Methods. 342 Caucasian male subjects aged ≤ 65 years with acute MI diagnosed according to WHO criteria, and 197 control subjects matched for age, gender, race and domicile were recruited from the Leeds General Infirmary, Leeds, UK. Fasting blood samples were taken at least 2 months after the acute event to minimise the bias of an acute phase response. Plasma CRP and C3 levels were determined by ELISA. Statistical analyses were carried out using SPSS v12, and data presented as mean (95% confidence intervals). Results. Complement C3 was significantly higher in patients with MI (1.19 [1.16, 1.22] g/L) compared with controls (0.99 [0.94, 1.03] g/L, p=0.001). CRP was also significantly higher in patients (1.41 [1.24, 1.60] mg/L) compared with controls (0.72 [0.61, 0.85], p=0.001). In a logistic regression model including C3, age, smoking, diabetes and hypertension, C3 was independently associated with MI; the odds ratios (ORs) for MI in subjects with C3 in quartiles 2, 3 and 4 compared to those with C3 in quartile 1 were: 2.65 [1.56, 4.50], 4.12 [2.36, 7.22] and 7.88 [4.20, 14.77] respectively. CRP was also independently associated with MI in a model including age, smoking diabetes and hypertension; the ORs for those with CRP in the 2nd, 3rd and 4th quartiles compared to the 1st were: 1.35 [0.80, 2.27], 2.01 [1.17, 3.45] and 2.49 [ 1.40, 4.42], respectively. To evaluate the combined effect of elevated C3 and CRP, subjects were classified into 4 groups according to whether C3 and CRP levels were above or below the median (1.12 g/L and 1.08 mg/L, respectively). 49% of controls and 21% of patients had C3 and CRP levels below the median, 22% of controls and 18% of patients had only CRP levels above the median, 15% of controls and 21% of patients had only C3 levels above the median and 14% of controls and 41% of patients had both CRP and C3 above the median. In a logistic regression model including age, smoking, diabetes and hypertension, compared to subjects with both C3 and CRP below the median, the odds ratio for MI in subjects with elevated CRP alone was 1.58 (0.92, 2.70), p=0.095, for elevated C3 alone was 3.06 (1.74, 5.40), p<0.001 and for elevated C3 and CRP was 4.79 (2.77, 8.28), p<0.001. Conclusion: These data suggest that elevated C3 is independently associated with MI and that evaluation of C3 in addition to CRP may be more beneficial than either inflammatory variable alone in assessing risk for MI.