Author summary Hypertension is a risk factor for cardiovascular disease and the most important risk factor for stroke. Family studies suggest that hypertension related traits are heritable. Previous genome-wide association studies (GWAS) have identified multiple common blood pressure (BP) variants but these variants do not overlap with the linkage evidence observed from family studies. Rare variants have been suggested to play a substantial role and contribute to missing heritability of BP. In this study, linkage analysis identified 16p13 linked to SBP in a cohort of 517 white individuals in 130 families from the Cleveland Family Study (CFS). By combining linkage and association analyses, we searched for rare, coding variants that can explain the linkage evidence. Rare, coding variants within RBFOX1 were associated with lower systolic (p-value = 0.00403) and diastolic (p-value = 0.0258) blood pressures, and explained significant amount of observed linkage evidence. We replicated the identified variants in four independent cohorts (with total sample size N = 57, 234) and further observed consistent evidence that rare RBFOX1 variants are protectively associated with blood pressure traits. Our study clearly shows that family-based designs are powerful for identifying rare, coding variants underlying complex diseases.