Elevated plasma fibrinogen levels represent an increased risk for cardiac events. This has enhanced the interest in identifying agents that can normalize elevated plasma fibrinogen levels. Agents that have this capacity are the lipid lowering fibric acid derivatives (e.g. ciprofibrate) and the platelet aggregation inhibitor ticlopidine. Fibrinogen is a very heterogenous molecule that has a number of different functions. Fibrinogen is an important protein in the coagulation process. Besides that, the concentration of fibrinogen is the main determinant of the plasma viscosity. The functionality of fibrinogen is partly determined by the molecular weight (MW) form of fibrinogen: the high MW (HMW) form clots faster than the low and low' (LMW and LMW) forms. The mechanism of the fibrinogen decrease by fibrates and ticlopidine has not yet been elucidated and, therefore, we studied the effects of treatment with these drugs on functional fibrinogen, fibrinogen antigen and (HMW+LMW) levels. The effect of ticlopidine was studied in 26 healthy volunteers and in 26 patients with stable angina pectoris. The effect of ciprofibrate was studied in 51 hypercholesterolemic patients. In the healthy volunteers, the mean (SD) baseline level of functional fibrinogen was 2.35 g/L (SD 0.35), for fibrinogen antigen this was 2.49 g/L (SD 0.63), and for (HMW+LMW) fibrinogen 1.97 g/L (SD 0.53). After 4 weeks of ticlopidine administration, the functional fibrinogen level had decreased with 0.20 g/L (9%, p=0.005 using the paired Student t-tesl), whereas the fibrinogen antigen levels had not significantly changed. In the stable angina patients, the mean (SD) baseline levels of functional plasma fibrinogen was 3.44 g/L (SD 0.61), fibrinogen antigen 2.60 g/L (SD 0.49) and for (HMW+LMW) fibrinogen 2.70 g/L (SD 0.60). These baseline fibrinogen levels were significantly higher than in the volunteer group. After four weeks ticlopidine administration the functional fibrinogen levels had decreased with 0.39 g/L (11%, p<0.005), whereas the fibrinogen antigen and (HMW+LMW) fibrinogen levels had not significantly changed. In the hypercholesterolemic group, the mean (SD) baseline level of functional fibrinogen was 3.38 g/L (SD0.61), for (HMW+LMW) fibrinogen this was 3.04 (SD 0.80). After 12 weeks of treatment with ciprofibrate, the functional fibrinogen levels were significantly decreased to 2.42 g/L (SD 0.42) (p<0.0005), whereas the (HMW+LMW) fibrinogen levels had not significantly changed. Therefore, the fibrinogen lowering effect of ticlopidine and ciprofibrate are likely to be a modulation of the functionality of the molecule. © Pearson Professional Ltd 1996.