Frailty is more prevalent among venous thromboembolism (VTE) patients. However, the relationship between long-term VTE risk and frailty remained unexplored. This study included 315 523 participants recruited from UK Biobank between 2006 and 2010. Frailty status of participants at recruitment was evaluated by physical frailty and frailty index. The association between frailty and long-term risk of VTE was assessed through Cox proportional models. After excluded participants without genetic data, we further explored the interaction and joint effect between frailty and genetic risk in 258 461 participants. Mediation analyses were performed to investigate whether frailty mediates the association between cancer, obesity, and VTE. Results revealed significant associations between frailty and increased risk of VTE (physical frailty: HR, 1.63; 95% CI, 1.49-1.78; frailty index: HR, 1.66; 95% CI, 1.53-1.78). Participants with high genetic risk and frailty exhibited the highest VTE risk (physical frailty: HR, 3.83; 95% CI, 3.22-4.55; frailty index: HR, 3.96; 95% CI, 3.41-4.62). Frailty and genetic risk exhibited a significant additive interaction, with a relative excess risk due to interaction (RERI) of 0.76 in the physical frailty cohort, and a RERI of 1.11 in the frailty index cohort. Frailty mediated approximately 14% of the association between cancer and VTE, and 9% of the association between obesity and VTE. In conclusion, frailty is significantly associated with an increased long-term risk of VTE in the general population. Combining frailty and genetic risk can assist in the identification of high-risk VTE populations. Also, frailty significantly mediates the association between cancer, obesity, and VTE.