Background Though drugs binding to serotonergic 5-HT2A receptors since long have been claimed to influence human anxiety, it remains unclear if this receptor subtype is best described as anxiety-promoting or anxiety-dampening. Whereas conditioned fear expressed as freezing in rat is modified by application of 5-HT2A-acting drugs locally into different brain regions, reports on the effect of systemic administration of 5-HT2A receptor agonists and 5-HT2A antagonists or inverse agonists on this behaviour remain sparse. Methods We assessed the possible impact of systemic administration of 5-HT2A receptor agonists, 5-HT2A receptor inverse agonists, and a selective serotonin reuptake inhibitor (SSRI) – per se or in combination – on the freezing displayed by male rats when re-exposed to a conditioning chamber in which they had received foot shocks seven days earlier. Results The 5-HT2A receptor agonists psilocybin and 25CN-NBOH induced a reduction in conditioned fear that was countered by pretreatment with 5-HT2A receptor inverse agonist MDL 100907. While both MDL 100907 and another 5-HT2A receptor inverse agonist, pimavanserin, failed to impact freezing per se, both compounds unmasked a robust fear-reducing effect of an SSRI, escitalopram, which by itself exerted no such effect. Conclusions The results indicate that 5-HT2A receptor activation is not a prerequisite for normal conditioned freezing in rat but that this receptor subtype, when selectively over-activated prior to expression, exerts a marked fear-reducing influence. However, in the presence of an SSRI, the 5-HT2A receptor, on the contrary, appears to counter an anti-freezing effect of the enhanced extracellular serotonin levels following reuptake inhibition.