Aims To study whether desensitization occurs after long-term administration of the b 1 -adrenoceptor partial agonist xamoterol and, if so, whether this can be influenced by ketotifen. Methods In a double-blind, randomized design 10 young, healthy males received ketotifen (2×1 mg day −1 p.o.) or placebo for 3 weeks with xamoterol (2×200 mg day −1 p.o.) administered concomitantly during the last 2 weeks. b 1 -adrenoceptor mediated responses were assessed as exercise-induced tachycardia and isoprenaline-induced shortening of heart rate corrected electromechanical systole (QS 2 c); isoprenaline-induced tachycardia was measured as a mixed b 1 -/b 2 -adrenoceptor-mediated effect.Results The first dose of xamoterol significantly increased resting heart rate and systolic blood pressure and significantly shortened QS 2 c. The last dose of xamoterol after 2 weeks of treatment still produced the same responses. Ketotifen did not influence these effects of xamoterol on resting haemodynamics. The first dose of xamoterol caused a rightward shift of the exercise-and isoprenaline-induced tachycardia (mean dose ratios±s.e.mean: 1.20±0.05 and 2.46±0.23) and the isoprenaline-evoked shortening of QS 2 c (dose ratio 3.59±0.68). This rightward shift was even more pronounced after 2 weeks xamoterol treatment. This additional rightward shift after 2 weeks of xamoterol was not affected by ketotifen (mean difference (95% CI) of log transformed dose ratios between placebo and ketotifen: exercise tachycardia 0.001 (−0.03; 0.04); isoprenaline tachycardia 0.03 (−0.15; 0.21); isoprenaline induced shortening of QS 2 c 0.13 (−0.22; 0.48)). Conclusions In humans xamoterol is a partial b 1 -adrenoceptor agonist with positive chrono-and inotropic effects at rest and antagonistic properties under conditions of b-adrenoceptor stimulation. These effects were well maintained after chronic dosing with no signs of b 1 -adrenoceptor desensitization. Ketotifen does not change the b-adrenoceptor mediated responses of xamoterol after chronic dosing.