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The mitogenic neurotransmitter, serotonin (5‐HT) acts as a growth factor for different types of non‐tumoral cells (e.g. vascular smooth muscle cells) and tumor cells (e.g. pancreatic carcinoid cells). The 5‐HT1A is a prototype receptor of 5‐HT1 family and as a G‐protein coupled receptor (GPCR), it exerts inhibitory action through Gi/o subunits and activating response via βγ subunits. 5‐HT1A receptors have long been implicated in the treatment of anxiety and depressive disorders. Apart from its role in neuropsychiatric diseases, 5‐HT1A receptor mediated signaling is important for T and B cell proliferation since blocking of the receptor has been linked to a reduced in vitro proliferative response after mitogenic stimulation. Here, we investigated the phenotypical and molecular effects of serotonin signaling by treating human B cell‐derived lymphoma cell lines with a selective 5‐HT1A antagonist. Our data show that repeated treatments with the 5‐HT1A antagonist resulted in significantly reduced proliferation in human B‐derived lymphoma cell lines. We demonstrate that the block in proliferation was associated with induction of apoptosis, DNA damage and morphological alterations of surviving cells. We also provide evidence that treatment of lymphoma B cells with the 5HT1A antagonist leads to activation of GSK3‐beta and a downregulation of c‐MYC and cyclin D1 mRNA transcripts. Collectively, our data indicate that modulation of serotonin signaling may have potential for treatment of B cell‐derived lymphomas.