The degradation and biological role of the cyclic pyrimidine nucleotide cCMP is largely elusive. We investigated nucleoside 3′,5′‐cyclic monophosphate (cNMP) specificity of six different recombinant phosphodiesterases (PDEs) by using a highly‐sensitive HPLC–MS/MS detection method. PDE7A1 was the only enzyme that hydrolyzed significant amounts of cCMP. Enzyme kinetic studies using purified GST‐tagged truncated PDE7A1 revealed a cCMP K M value of 135 ± 19 μM. The V max for cCMP hydrolysis reached 745 ± 27 nmol/(min mg), which is about 6‐fold higher than the corresponding velocity for adenosine 3′,5′‐cyclic monophosphate (cAMP) degradation. In summary, PDE7A is a high‐speed and low‐affinity PDE for cCMP.