Using bioinformatics approaches and high-throughput transcriptomic data of ADAR knockdown cells, we globally examined how ADAR and its A-to-I RNA editing activity influence alternative mRNA splicing. Our global analysis reveals that ADAR plays a major role in splicing regulation. Editing sites are enriched in alternatively spliced exons and splicing regulatory elements, but the primary mechanism for ADAR-mediated regulation of alternative splicing is modulation of trans-acting factors involved in the splicing machinery.