Objective: The aim of this clinical trial was to assess the effect of resin infiltration on the progression of proximal caries lesions. Subjects and Methods: Forty-one patients, aged between 15 and 33 years, with 2 or more non-cavitated proximal caries lesions were included. In 41 of the adolescent and young adults, 45 pairs of proximal lesions with radiological extension into the inner and outer half of the enamel, or into the outer third of the dentin, were randomly allocated to the test groups (resin infiltration application + fluoridated toothpaste and flossing use) or to the control group (fluoridated toothpaste and flossing use). Standardized geometrically aligned digital bitewing radiographs were obtained using individual biting holders. The radiographic progression of the lesions was assessed after 1 year by digital-subtraction radiography. The McNemar test was used for statistical analysis. Results: In the test group 1/45 of the lesions (2.2%) and in the control group 9/45 of the lesions (20%) showed progression. The caries progression rate of the control group was significantly higher than that of the test group (p < 0.05). Conclusions: Resin infiltration of proximal caries lesions is effective in reducing progression of the lesion.