Antisense oligomers (AOs) are short, single-stranded nucleic acid sequences that may anneal to a mRNA or pre-mRNA by complementary base pairing and, depending on the base and backbone chemistries, can induce a variety of mechanisms to alter the gene expression. We have designed AOs to redirect the splicing process and have used this strategy to by-pass disease-causing mutations in the dystrophin gene (DMD) by inducing a specific exon-skipping to restore the reading frame. When developing a panel of AOs to skip all dystrophin exons, remarkably we found that one in three AOs appeared to be completely ineffective. In this study, we modified the composition of some ineffective AOs and increased their annealing potential by incorporating locked nucleic acid residues into the sequences. AOs targeting the skipping of exon 16, 23 and 51 of human DMD transcripts were synthesized as two different chemistries, 2’-O-methyl (2’-OMe) oligomers and locked nucleic acid (LNA)/2’-OMe mixmers. Primary human myoblasts were treated with 2’-OMe or LNA/2’-OMe AOs, and the DMD transcripts were analysed for exon skipping. The 2’-OMe AOs showed no significant exon skipping while all the LNA/2’-OMe mixmers exhibited skipping of the targeted exons. Interestingly, the LNA/2’-OMe mixmer targeting exon 51 induced two additional transcripts, representing incomplete skipping of exon 51 with retention of 95 or 188 bases from the beginning of exon 51. These results indicate that LNA/2’-OMe mixmers may be more efficient at exon skipping, but this improvement may come at the cost of activating alternate cryptic splice sites.