5-HT_2A, a G-protein coupled receptor, is widely expressed in the human body, including in the gastrointestinal tract, platelets and the nervous system. It mediates various functions, for e.g. learning, memory, mood regulation, platelet aggregation and vasoconstriction, but its involvement in cell-adhesion remains largely unknown. Here we report a novel role for 5-HT_2A in cell-matrix adhesion.In HEK293 cells, which are loosely adherent, expression and stimulation of human or rat 5-HT_2A receptor by agonists such as serotonin or 2,5-dimethoxy-4-iodoamphetamine (DOI) led to a significant increase in adhesion, while inhibition of 5-HT_2A by antipsychotics, such as risperidone, olanzapine or chlorpromazine prevented it. 5-HT_2A activation gave rise to stress fibers in these cells and was also required for their maintenance. Mechanistically, the 5-HT_2A-mediated adhesion was mediated by downstream PKC and Rho signaling. Since 5-HT_2A is associated with many disorders such as dementia, depression and schizophrenia, its role in cell-matrix adhesion could have implications for neural circuits.