The role of many splicing factors in pre-mRNA splicing and the involvement of these factors in the processing of specific transcripts have often been defined through the analysis of loss-of-function mutants in vivo. Here we show that inactivating the nonsense-mediated mRNA decay (NMD) results in an enhancement of splicing phenotypes associated with several S. cerevisiae splicing factor mutations. Tiling microarrays showed that inactivation of the NMD factor Upf1p in the prp17Delta and prp18Delta mutant strains results in a larger spectrum of splicing defects than what is observed in the single mutants, including new transcripts previously shown unaffected by Prp17p or Prp18p inactivation. Inactivation of Upf1p in the second step/recycling factor prp22-1 mutant and in the nam8Delta and mud1Delta U1 snRNP component mutants also increase unspliced precursor accumulation of several specific transcripts. In addition, deletion of UPF1 partially suppresses the growth defects associated with the prp17Delta or prp22-1 mutations, demonstrating a positive genetic interaction between NMD and splicing factor mutants. These results show that RNA surveillance by NMD can mask some of the effects of splicing factor mutations, and that the roles of splicing factors cannot be fully understood in vivo unless RNA degradation systems that degrade unspliced precursors are also inactivated.