Background In patients with multiple sclerosis (MS), disability and autoinflammatory processes may result in an increased risk of venous thromboembolism (VTE) Objective To evaluate the risk of VTE associated with MS. Methods We conducted an observational-cohort study within the Clinical Practice Research Datalink (1987-2009) linked to the National Registry of Hospitalizations (1997-2008). At the time of MS diagnosis, a comparison cohort (N=33370) without a recorded MS diagnosis during the study period was matched (6:1) to the MS cohort (n=5566) by birth year, sex, and practice. Subjects were followed from the index date until the occurrence of VTE, end of data collection, migration, or death, whichever came first. Cox proportional-hazards models were used to derive adjusted hazard ratios and 95% confidence intervals for VTE associated with MS and VTE risk factors within the MS cohort. Time-dependent adjustments were made for age, comorbidity, and medication use. Results Compared with the comparison cohort, a 2.6-fold increased risk of VTE was observed for MS patients (adjusted hazard ratio 2.56, 95% confidence interval 2.06-3.20). A prior VTE event, varicose veins, obesity, and major trauma were found to be associated with an increased risk of VTE within the MS population. Moreover, the risk of VTE was increased in MS patients with recent records indicating immobility, spasticity, glucocorticoid use, or disability. Conclusions Patients with MS had an increased risk of VTE. Furthermore, our results provide evidence that this association is, at least in part, mediated through an increased prevalence of VTE risk factors in MS patients.