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This study investigates the interactions of sibutramine, a hypophagic drug non‐selective inhibitor of norepinephrine (NE) and 5‐HT uptake, with the α₁‐ARs subtypes of the rat vas deferens (α_1A), spleen (α_1B) and aorta (α_1D) and with human α₁‐ARs subtypes expressed in HEK 293 cells. Sibutramine potentiated the contractions induced by NE in the vas deferens, consistent with an indirect sympathomimetic action. In the rat spleen, sibutramine (up to 100 μM) was unable to affect the contractions induced by NE, suggesting it is inactive at α_1B‐ARs. In rat aorta sibutramine 3 to 100 μM competitively antagonized the contractions induced by NE (Schild slope = 0.95 ± 0.05; pA₂ = 5.5 ± 0.1) indicating it interacts with α_1D‐ARs. Sibutramine inhibited the specific binding of [³H]‐prazosin to membranes from HEK cells expressing α_1A‐ARs and α_1B‐ARs with very low affinities (pK_i ≈ 3.5). Low concentrations of sibutramine …