Human parainfluenza virus type 1 (HPIV1) is an important pediatric respiratory pathogen, and its virulence in vivo can be attenuated by introducing mutations into the C gene, a strategy that has been used to design live attenuated candidate vaccines. By tracking gene expression over time, we found that a HPIV1 mutant with a single point mutation in the C gene, referred to as C(F170S), and a HPIV1 mutant with complete deletion of the C gene, referred to as P(C-), altered the expression of over 1000 genes, in sharp contrast to wild-type (WT) HPIV1. Using functional bioinformatics, we found that binding sites for the IRF and NF-kB family of transcription factors were over-represented in many of the C protein targeted pathways. By examining the activation of the major components of the type I interferon (IFN) enhanceosome, we found that the C mutant viruses, but not WT HPIV1, activated IRF3 phosphorylation and IkBB degradation, steps integral to the formation of the interferon enhanceosome. To investigate the basis for the observed antagonism of the host response by the WT C proteins, which are expressed from the C open reading frame as a nested set of carboxy-coterminal proteins, we searched for but were unable to identify C-interacting proteins among members of the RIG-I/MDA5 pathway. Furthermore, we also found that the WT C proteins supplied in trans could block IFNB induced by P(C-) HPIV1 infection but not by heterologous inducers of RIG-I and MDA5, namely RSV and poly I:C, respectively. These two lines of evidence suggested that the HPIV1 C proteins do not directly block type I IFN production, such as by interacting with a host factor of the RIG-I/MDA5 pathway. Using knockout mouse embryonic fibroblasts, we found that HPIV1-induced IFNB production relied mainly on MDA5. Consistent with this observation, a striking amount of intracellular dsRNA was detected during infection with the C mutant HPIV1 viruses but not with WT HPIV1. A marked increase in viral genome, antigenome, and mRNA as well as a decrease in viral protein accumulation provided compelling evidence for dysregulated viral RNA synthesis and an inhibition of viral protein synthesis in the absence of WT C proteins. We suggest that this resulted in an imbalance in the N protein-to-genomic RNA ratio, leading to incomplete encapsidation and an intracellular environment permissive for the generation of dsRNA. PKR activation followed the kinetics of dsRNA accumulation and contributed to both IFNB induction and the reduction in viral protein levels. This study establishes the profound effects that the C proteins of wild-type HPIV1 play in evading the host response to HPIV1 infection, and it extends our current understanding of the innate immune response to HPIV1 infection.