Background The Illumina family of Infnium Methylation BeadChip microarrays has been widely used over the last 15 years for genome-wide DNA methylation profling, including large-scale and population-based studies, due to their ease of use and cost efectiveness. Succeeding the popular HumanMethylationEPIC BeadChip (EPICv1), the recently released Infnium MethylationEPIC v2.0 BeadChip (EPICv2) claims to extend genomic coverage to more than 935,000 CpG sites. Here, we comprehensively characterise the reproducibility, reliability and annotation of the EPICv2 array, based on bioinformatic analysis of both manifest data and new EPICv2 data from diverse biologi‑ cal samples. Results We fnd a high degree of reproducibility with EPICv1, evidenced by comparable sensitivity and precision from empirical cross-platform comparison incorporating whole genome bisulphite sequencing (WGBS), and high correlation between technical sample replicates, including between samples with DNA input levels below the manu‑ facturer’s recommendation. We provide a full assessment of probe content, evaluating genomic distribution and changes from previous array versions. We characterise EPICv2’s new feature of replicated probes and provide recommendations as to the superior probes. In silico analysis of probe sequences demonstrates that probe crosshybridisation remains a signifcant problem in EPICv2. By mapping the of-target sites at single nucleotide resolution and comparing with WGBS we show empirical evidence for preferential of-target binding. Conclusions Overall, we fnd EPICv2 a worthy successor to the previous Infnium methylation microarrays, however some technical issues remain. To support optimal EPICv2 data analysis we provide an expanded version of the EPICv2 manifest to aid researchers in understanding probe design, data processing, choosing appropriate probes for analysis and for integration with methylation datasets from previous versions of the Infnium Methylation BeadChip. [ABSTRACT FROM AUTHOR]