Cyclic nucleotide phosphodiesterases (PDEs) work in conjunction with adenylate/guanylate cyclases to regulate the key second messengers of G protein-coupled receptor signaling. Previous attempts to determine the full-length structure of PDE family members at high-resolution have been hindered by structural flexibility, especially in their linker regions and N- and C-terminal ends. Therefore, most structure-activity relationship studies have so far focused on truncated and conserved catalytic domains rather than the regulatory domains that allosterically govern the activity of most PDEs. Here, we used single-particle cryo-electron microscopy to determine the structure of the full-length PDE6 alpha beta 2 gamma complex. The final density map resolved at 3.4 angstrom reveals several previously unseen structural features, including a coiled N-terminal domain and the interface of PDE6 gamma subunits with the PDE6 alpha beta heterodimer. Comparison of the PDE6 alpha beta 2 gamma complex with the closed state of PDE2A sheds light on the conformational changes associated with the allosteric activation of type I PDEs.