The genetic defect of coagulation factor V, known as factor V Leiden, produces a resistance to degradation by activated protein C and increased venous thrombosis. However, the role of factor V Leiden in the formation of left atrial thrombus with nonrheumatic atrial fibrillation has not been studied. We investigated whether factor V Leiden is a risk factor for left atrial thrombus in patients with nonrheumatic atrial fibrillation. We analyzed clinical, echocardiographic, and biochemical data in 105 consecutive patients with nonrheumatic atrial fibrillation. These patients were divided into two groups: group A (n = 37) with left atrial thrombus and group B (n = 68) without left atrial thrombus. The study also included 42 control subjects. Left atrial thrombus was investigated by using both transthoracic echocardiography and transesophageal echocardiography. Blood samples from the patients and controls were analyzed for the factor V Leiden mutation by DNA analysis, using the polymerase chain reaction. There was no significant difference in the prevalence of factor V Leiden between the patients and control subjects. The prevalence of factor V Leiden mutation was 8.1% (3/37) in patients with left atrial thrombus, and 8.8% (6/68) in patients without left atrial thrombus. The prevalence of factor V Leiden was 7.1% (3/42) in control subjects. The prevalance of factor V Leiden was 10% (2/20) in patients with spontaneous echo contrast and 8% (7/85) in patients without spontaneous echo contrast. Multivariate analyses showed that left ventricular ejection fraction was an independent predictor of left atrial thrombus. Factor V Leiden mutation is not a risk factor for left atrial thrombus formation and spontaneous echo contrast in patients with nonrheumatic atrial fibrillation.