Background: The definition of dental hypersensitivity is “pain derived from exposed dentin in response to chemical, thermal tactile or osmotic stimuli which cannot be explained as arising from any other dental defect or disease”. One of the treatments proposed is tubular occlusion. The aim of this in vivo split-mouth randomized clinical trial was to evaluate the clinical efficacy of a in-office application of a fluoride varnish (Bifluorid 10) and a bonding resin (Futurabond U) in adults with dentin hypersensitivity. Material and methods: A total of 180 teeth were treated with Bifluorid 10 and 160 with Futurabond U. Outcome measurements were taken one or two weeks before treatment, at baseline at the application days, at 1 week and at 1–6 months after first treatment. Results: Both treatments reduced pain intensity. Bifluorid 10 and Futurabond U have similar efficacy in reducing SCHIFF-measured pain reduction, while Bifluorid 10 is significantly more efficient for VAS-measured pain reduction, mainly due to long-term pain reduction. Patient age has a significant negative influence on pain reduction, while the influence of patient gender and BEWE of the tooth is insignificant. Conclusions: Bifluorid 10 and Futurabond U are effective in the treatment of dental hypersensitivity. The RCT was registered at the US National Institutes of Health (ClinicalTrials.gov) #NCT04813848.