OBJECTIVE Aim of the study was to compare how six different sealants resisted thermal, mechanical, and chemical loading in vitro. METHODS In all, 120 extracted human, nondecayed molars were divided into six groups (20 samples each) and embedded in resin blocks. The buccal surfaces of the tooth samples were polished and divided into three areas. Area A contained the product to be analyzed, area B was covered with colorless nail varnish (negative control), and area C remained untreated (positive control). The samples were stored in 0.1% thymol solution. To simulate a 3-month thermomechanical load, the samples were subjected to thermal cycling and a cleaning device. After 7 days incubation in a ten Cate demineralization solution (pH value: 4.6), the samples were dissected using a band saw and the lesion depths and demineralization areas were evaluated and compared microscopically. RESULTS The tooth surfaces treated with PRO SEAL® showed no demineralization. Mean lesion depths of 108.1, 119.9, 154.9, 149.2, and 184.5 μm were found with Alpha-Glaze®, Seal&Protect®, Tiefenfluorid®, Protecto®, and Fluor Protector, respectively. There was a significant difference between PRO SEAL® and the other products (p > 0.0001). There was no significant difference between the other products. CONCLUSIONS PRO SEAL® resisted thermal, mechanical, and chemical loading in vitro, providing protection against white spot lesions.