Gene-gene interactions likely contribute to the etiology of multifactorial diseases such as cerebral venous thrombosis (CVT) and could be one of the main sources of known missing heritability. We explored Factor ( ) and gene interactions among patients with CVT. Patients with CVT of European ancestry from the large Bio-Repository to Establish the Aetiology of Sinovenous Thrombosis (BEAST) international collaboration were recruited. Codominant modelling was used to determine interactions between genome-wide identified and genes with CVT status. We studied 882 patients with CVT and 1,205 ethnically matched control participants (age: 42 ± 15 vs 43 ± 12 years, = 0.08: sex: 71% male vs 68% female, = 0.09, respectively). Individuals heterozygous (AT) for the risk allele (T) at both loci (rs56810541/ and rs8176645/ ) had a 3.9 (95% CI 2.74-5.71, = 2.75e-13) increase in risk of CVT. Individuals homozygous (TT) for the risk allele at both loci had a 13.9 (95% CI 7.64-26.17, = 2.0e-15) increase in risk of CVT. The presence of a non-O blood group (A, B, AB) combined with TT/rs56810541/ increased CVT risk by OR = 6.8 (95% CI 4.54-10.33, = 2.00e15), compared with blood group-O combined with AA. Interactions between factor and genes increase risk of CVT by 4- to 14-fold.