<p>Transient receptor potential melastatin type 2 (TRPM2) is a nonselective cation channel involved in synaptic plasticity. We investigated its role in contextual fear conditioning and extinction of conditioned fear using <i>Trpm2-</i>deficient (<i>Trpm2</i>^{<i>−/−</i>}) mice. <i>Trpm2</i>^{<i>−/−</i>} mice exhibited reduced acquisition of contextual fear memory during conditioning but had an intact freezing response to conditioning context 24&#xa0;h after conditioning. They also showed a reduced freezing response to extinction training, indicating facilitated extinction. Consistent with this, infusion of flufenamic acid (FFA), a TRPM2 antagonist, into the dentate gyrus (DG) of the hippocampus in fear-conditioned mice facilitated extinction of contextual fear. The enhanced extinction in <i>Trpm2</i>^{<i>−/−</i>} and FFA-treated mice was associated with down-regulation of immediate-early genes (IEGs) including <i>Npas4, c-Fos, Arc</i> and <i>Egr1</i> in the hippocampus after extinction training. Our results indicate that TRPM2 plays a positive role in retention of contextual fear memory by modulating neuronal activity in the hippocampus, and suggest that TRPM2 activity could potentially be targeted to strengthen extinction-based exposure therapies for post-traumatic stress disorder (PTSD).</p>