The accuracy of replication, transcription and translation depends on the correct pairing of complementary bases of nucleic acids. However, sequence dependent structural variations of double helices may interfere with the fidelity of these processes in altering base pair conformations. Irregular conformations of the template-primer DNA duplex can induce replication errors in altering the structure of the polymerase active site. However, in most DNA polymerases, water exclusion induces the duplex to adopt the A-conformation. In attenuating the structural variability, the A-form enhances replication fidelity. How hydration and DNA sequence modulate the structure of A-DNA is therefore a relevant question for better understanding the mechanisms of sequence directed mutagenesis. This study is focused on the relationships between hydration and the distortion of A-DNA double helices. The crystallographic analysis of the hydration pattern of A-DNA decamers reveals that the subtle interplay of DNA sequence and hydration helps to stabilize unusual structures. These findings are discussed in the context of the accuracy of replication.