Methylation of a CpG island is a faithful marker of silencing of its associated gene. Different approaches report the methylation status of a CpG island based on the determination of one or a few CpG sites by assuming the homogeneity of methylation along the element. This strategy is frequently applied in both locus-specific and genome-wide studies, but often without a validation of the representativeness of the interrogated CpG site compared with the whole element. We have evaluated the predictive informativeness of the HpaII sites located in CpG islands using data from high-resolution methylome maps, which offer the possibility to assess the methylation homogeneity of each CpG island and to determine the reporter accuracy of single sites as surrogate markers. An excellent correlation was observed between the HpaII and CpG island methylation levels (r > 0.93). At the qualitative level, the predictive sensitivity of HpaII was >95% with >92% specificity for methylated CpG islands and >90% sensitivity with >95% specificity for unmethylated CpG islands. This analysis provides a global validation framework for strategies based on the use of the methylation-sensitive HpaII restriction enzyme.