Stachys pilifera Benth has long been used to treat infectious diseases as well as respiratory and rheumatoid disorders in Iranian folk medicine. Antioxidants, antitumor, and antimicrobial properties of the plant have been reported. This experimental study was designed to evaluate systemic and topical anti-inflammatory effects of the hydro-alcoholic extract from aerial parts of Stachys pilifera (HESP). Anti-inflammatory effects of HESP was studied in four well-known animal models of inflammation, including carrageenan- or formalin-induced paw edema in rat (thirteen groups, 6 rats per each group), and 12-O-tetradecanoylphorbol-13-acetate (TPA)- or xylene-induced ear edema in mouse (ten groups, 6 mice per each group). The rats received HESP (50-400 mg/ kg) orally 45 minutes before the subplantar injection of carrageenan or formalin. In TPA or xylene tests, HESP (1, 2.5, and 5 mg/ear) was applied topically simultaneous with these phlogistic agents on the ear mice. Finally, pathological examination of the inflamed tissues (paw and ear) was carried out. Acute toxicity study of the extract showed that no rats were killed at 5000 mg/kg (LD50 > 5000 mg/kg). The extract (100 and 200 mg/ kg) significantly suppressed carrageenan-induced paw edema 1, 2, 3, and 4 hours after carrageenan challenge in comparison with the control group (P < 0.001). The HESP (100 and 200 mg/kg) also produced a considerable antiedematogenic effect in the formalin test over a period of 24 hours (P < 0.01). Furthermore, topical administration of the HESP (1, 2.5, and 5 mg/ear) inhibited TPA- and xylene-induced ear edema in comparison with the control group (P < 0.001). The pathological analysis of the paws and ears revealed that HESP was capable of reducing tissue destruction, cellular infiltration, and subcutaneous edema induced by the indicated phlogistic agents. The present data confirmed systemic and topical anti-inflammatory effects of Stachys pilifera which is comparable to indomethacin.