A strong, independent and positive association between plasma fibrinogen concentrations and cardiovascular disease has been established. To determine if phenytoin lowers fibrinogen levels we measured plasma fibrinogen levels in a subset of participants enrolled in a randomized, placebo-controlled, double-blind clinical trial. Participants received placebo or 100 mg, 200 mg, or 300 mg/day of phenytoin for 14 weeks. Fifty-six subjects had post-treatment and 20 had pre- and post-treatment fibrinogen measurements. The phenytoin-treated subjects with post-treatment measurements had a 0.24 g/l (8%) reduction in mean fibrinogen levels compared to placebo (p = 0.3). Phenytoin may be capable of producing meaningful reductions in fibrinogen levels.