Cannabinoid receptor (CB1) ligands decrease excitatory and inhibitory transmission in the hippocampus, but the influence of endogenously formed cannabinoids (eCBs) on basal excitatory transmission remains uncertain. Here, we investigated the influence of eCBs on synaptic transmission in CA1 hippocampus using the slice preparation. Blockade of CB1 with the selective receptor antagonists SR141716 (rimonabant) or AM251 augmented synaptic responses evoked upon stimulation of the Schaffer collaterals. This effect persisted in the presence of bicuculline or CGP55845 to block GABA(A) or GABA(B) receptors, revealing a tonic eCB influence on excitatory transmission. Selective inhibition of cyclooxygenase-2 (COX-2) with meloxicam or NS-398 decreased excitatory responses partly in a CB1-dependent manner, independently of GABA(A) transmission. Paired-pulse paradigms suggested a presynaptic CB1 mechanism to decrease glutamate release. Inhibition of COX-1 or other routes of eCB degradation did not affect synaptic transmission. We conclude that COX-2 regulates the formation of CB1 ligands that decrease hippocampal excitatory transmission.