1. The principal aim of the present study was to determine whether long-term treatment of human lung mast cells (HLMC) with the clinically-relevant β 2-adrenoceptor agonists, salbutamol and terbutaline, leads to desensitization of β 2-adrenoceptor-mediated responses in these cells. 2. The non-selective β-adrenoceptor agonist, isoprenaline, and the selective β 2-adrenoceptor agonists, salbutamol and terbutaline, inhibited the IgE-mediated release of histamine from HLMC. Salbutamol (pD 2; 7.7±0.3) and terbutaline (pD 2; 7.34±0.2) were roughly equipotent as inhibitors of histamine release although both agonists were less potent than isoprenaline (pD 2; 8.64±0.2). 3. Isoprenaline (10 -5 M), salbutamol (10 -5 M) and terbutaline (10 -5 M) enhanced total cell cAMP levels in HLMC over basal by 361±90, 150±38 and 165±35%, respectively. 4. Long-term exposure (24 h) of HLMC to either salbutamol (10 -7 M) or terbutaline (10 -7 M) led to a subsequent reduction in the effectiveness of salbutamol and terbutaline (both 10 -9 - 10 -4 M) to inhibit histamine release. However, salbutamol was significantly (P < 0.05) more effective than terbutaline at promoting the functional desensitization. 5. Radioligand binding studies, using iodinated cyanopindolol, were performed to determine β 2-adrenoceptor density in cell membranes after pretreatment (24 h) of cells with either salbutamol (10 -6 M) or terbutaline (10 -6 M). Both agonists reduced β 2-adrenoceptor density in membranes to about the same extent (∼25% reduction) but these changes in receptor density were not statistically significant (P > 0.05). 6. These data indicate that long-term exposure of mast cells to salbutamol causes greater levels of desensitization to β 2-adrenoceptor-mediated responses in HLMC than terbutaline. These findings may have wider clinical significance in the context of asthma treatment as compromised mast cell inhibition could result following long-term exposure of mast cells to short-acting bronchodilators.