AIM: 5-aza-2'deoxycytidine (Aza) is used to treat myelodysplastic syndrome and is in trials for other cancers. It acts chiefly as a hypomethylating agent inhibiting DNMT1. A lack of understanding of off-target effects in normal cells hinders wider usage. MATERIALS & METHODS: We compared treatment of the same normosomic, nontransformed fibroblast cell line with Aza and SMARTpool siRNA against DNMT1. Methylation and transcription were assayed using Illumina 450k and HT12 arrays. RESULTS: Both Aza and DNMT1 siRNA caused overall hypomethylation, with siRNA more efficient at demethylating gene bodies. Hypomethylation at the promoters of many histones, and hypermethylation at multiple sites genome wide, were unique to Aza treatment. CONCLUSION: Aza had important unique effects and targets compared with DNMT1 inhibition via siRNA.