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As of 2020, use of beta2‐agonist salmeterol is restricted by the World Anti‐Doping Agency (WADA) and is only permitted by inhalation at therapeutic doses not exceeding 200 μg in 24 h. In contrast to beta2‐agonists salbutamol and formoterol, WADA has not established a urine threshold for salmeterol despite its muscle hypertrophic actions observed in animals. Herein, we investigated plasma (0–4 h) and urine (0–24 h) concentrations (by ultra‐high‐performance liquid chromatography–tandem mass spectrometry [UHPLC–MS/MS]) of salmeterol and α‐hydroxysalmeterol after dry powder inhalation at supratherapeutic (400 μg) and high therapeutic (200 μg) doses, and after seven consecutive days of therapeutic inhalation (200 μg × day−1) in 11 healthy endurance‐trained men. During each trial, participants inhaled salmeterol before 1½ h moderate‐intensity cycling. Mean ± SD maximum urine concentrations of salmeterol unadjusted for specific gravity reached 4.0 ± 1.6, 2.1 ± 1.5, and 2.2 ± 1.1 ng × ml−1 for 400 μg, 200 μg, and seven consecutive days of 200 μg, respectively, with corresponding maximum urine concentrations of α‐hydroxysalmeterol being 11.6 ± 6.1, 5.7 ± 4.6, and 6.5 ± 2.6 ng × ml−1. Within the relevant window for doping control (first 6 h post‐inhalation), the present data (119 samples), along with 64 biobank urine samples, showed that a combined salmeterol and α‐hydroxysalmeterol urine threshold with equal cut‐offs of 3.3 ng × ml−1 was superior to a salmeterol‐only threshold to discriminate therapeutic (200 μg) from supratherapeutic use (400 μg) with a sensitivity of 24% with 0% false positives when applying the WADA technical document (TD2019DL.v2) method of specific gravity adjustment. Thus, a combination of urine salmeterol and α‐hydroxysalmeterol concentrations may be suitable for discriminating between therapeutic and supratherapeutic prohibited inhalation of salmeterol. [ABSTRACT FROM AUTHOR]