Abstract Background Tamoxifen, a selective estrogen receptor modulator, decreased airway neutrophilia and improved clinical signs in an experimental model of equine asthma, and induced neutrophilic apoptosis in vitro. Hypothesis/Objectives Tamoxifen reduces airway neutrophilia and improves lung function in severe asthmatic horses. Animals Twelve severe asthmatic horses from a research herd. Methods Randomized controlled blinded study design. The effects of a 12-day oral treatment with tamoxifen (0.22 mg/kg, q24h) or dexamethasone (0.06 mg/kg, q24h) on lung function, endoscopic tracheal mucus score and bronchoalveolar lavage fluid cytology were compared. Results Tamoxifen significantly improved the pulmonary resistance (RL; mean reduction of 1.15 cm H2O/L/s [CI: 0.29-2.01, P = .007] on day 13), but had no effect on the other variables evaluated. Dexamethasone normalized lung function (mean reduction of RL of 2.48 cm H2O/L/s [CI: 1.54-3.43, P < .0001] on day 13), without affecting airway neutrophilia. Conclusions and Clinical Importance Results of this study do not support the use of tamoxifen at the dose studied as an antineutrophilic medication in the treatment of asthmatic horses in chronic exacerbation.