The receptor involved in the serotonin (5-hydroxytryptamine [5-HT])-induced vasodilatation in the human forearm has not yet been identified. Experimental data point to the 5-HT2B receptor located on the endothelium. RS-127445 (2-amino-4-(4-fluoronaphthyl-1-yl)-6-isopropylpyrimidine) is a novel potent and selective 5-HT2B receptor antagonist. The effect of oral RS-127445 (500 mg) on 5-HT-induced vasodilatation was studied in a double-blind, randomized, placebo-controlled, crossover study in six healthy volunteers. On each study day 5-HT (0.5 ng/kg/min) was infused into the brachial artery for 8 min, before drug administration and at intervals of 20, 65, 110, 230, and 470 min after oral ingestion. At each infusion, plasma samples for study drug assay were taken and forearm blood flow was assessed using venous occlusion plethysmography. Although (log) drug concentrations exceeded pKi, there was no correlation between RS-127445 concentrations and 5-HT-induced vasodilatation. 5-HT-induced vasodilatation did not differ between treatments and time points. It appears that there is no functional involvement of 5-HT2B receptors in 5-HT-mediated vasodilatation in the human forearm.