Background Mitral regurgitation in people without prior cardiac disease is considered a degenerative disease with no established risk factors for its prevention. We aimed to test the hypothesis that elevated systolic blood pressure (SBP) across its usual spectrum is associated with higher risk of mitral regurgitation. Methods and findings We used linked electronic health records from the United Kingdom Clinical Practice Research Datalink (CPRD) from 1 January 1990 to 31 December 2015. CPRD covers approximately 7% of the current UK population and is broadly representative of the population by age, sex, and ethnicity. About 5.5 million UK patients with no known cardiovascular or valve disease at baseline were included in this cohort study. We investigated the relationship between blood pressure (BP) and risk of mitral regurgitation using Cox regression models. Our primary exposure variable was SBP and our primary outcome was incident reports of mitral regurgitation, which were identified from hospital discharge reports or primary care records. Of the 5,553,984 patients in the CPRD that met our inclusion criteria, during the 10-year follow-up period, 28,655 (0.52%) were diagnosed with mitral regurgitation and a further 1,262 (0.02%) were diagnosed with mitral stenosis. SBP was continuously related to the risk of mitral regurgitation with no evidence of a nadir down to 115 mmHg (p < 0.001). Each 20 mmHg increment in SBP was associated with a 26% higher risk of mitral regurgitation (hazard ratio [HR] 1.26; CI 1.23, 1.29). The observed association was partially mediated by diseases affecting the left ventricle during follow-up (myocardial infarction [MI], ischaemic heart disease [IHD], cardiomyopathy, and heart failure). However, the percentage of excess risk mediated (PERM) by these proximate causes of secondary mitral regurgitation was only 13% (CI 6.1%, 20%), and accounting for them had little effect on the long-term association between SBP and mitral regurgitation (mediator-adjusted HR 1.22; CI 1.20, 1.25; p < 0.001). Associations were similar for each 10 mmHg increment in diastolic blood pressure (DBP) (p < 0.001) or each 15 mmHg increment in pulse pressure (PP) (p < 0.001). By contrast, there was no association between SBP and risk of mitral stenosis (HR per 20 mmHg higher SBP 1.03; CI 0.93, 1.14; p = 0.58). These analyses are based on routinely collected data from health records which may be sensitive to measurement errors, and the observed associations may not be generalizable to less severe and subclinical cases of mitral regurgitation. Conclusions Long-term exposure to elevated BP across its whole spectrum is associated with an increased risk of primary and secondary mitral regurgitation. These findings suggest that BP control may be of importance in the prevention of mitral regurgitation.