To evaluate the preventive effect of glass ionomer cement (GIC) against dental caries and posteruptive breakdown (PEB) on molars affected by molar incisor hypomineralization (MIH). In this randomized clinical trial, 77 children aged 5–9 years with at least 1 MIH-affected molar and without PEB or dentin caries lesions (<i>n</i> = 228) were included and randomly allocated to one of the following groups: (1) MIH-affected molars that remained unsealed and (2) MIH-affected molars that received GIC sealants. Dental caries and PEB were clinically evaluated after 6 and 12 months. Associations between dental caries and PEB with independent variables were evaluated using logistic regression analysis (<i>p</i> &#x3c; 0.05). The MIH-affected molars allocated to the GIC sealant group were less likely to develop dental caries compared to those allocated to the unsealed group (OR = 0.23; 95% CI 0.06–0.95). Conversely, application of a GIC sealant was not associated with prevention of PEB (<i>p</i> = 0.313). Furthermore, MIH-affected molars presenting yellow-brown opacities were almost 5 times more likely to develop dental caries (<i>p</i> = 0.013) and PEB (<i>p</i> = 0.001) compared to those presenting white-creamy opacities. We can conclude that GIC sealants can prevent dental caries on MIH-affected molars; however, the same protective effect was not observed for PEB.