Substance P and the neurokinin-1 receptor often play a role in the pathophysiology of chronic refractory cough (CRC). In this trial, the efficacy and safety of orvepitant was determined in patients with CRC. Patients with excessive daytime coughing (> 3 to < 250 coughs/hour) received orvepitant 30 mg once daily for four weeks. Twenty-four hour cough frequency was measured at baseline and again at weeks one, four, and eight. The primary outcome was four-week change in daytime cough frequency; cough severity visual analogue scale (VAS) score, global ratings of change for cough frequency and severity, and Cough-specific Quality of Life Questionnaire score were all considered secondary outcomes. The study included 13 patients, all of whom completed the trial. Mean cough frequency at baseline was 71.4 coughs/hour. At week four, there was a reduction from baseline of 18.9 (26%) coughs/hour (95% confidence interval [CI], 9.6–28.3; P < 0.001). Improvement was observed as early as week one (reduction from baseline, 27 coughs [38%] coughs/hour; 95% CI, 11.4–42.7; P = 0.001). The effects continued after treatment cessation (week eight reduction from baseline, 20.4 [29%] coughs/hour; 95% CI, 3.2–37.5; P = 0.020). Cough severity VAS score and quality of life both substantially improved, and orvepitant was considered safe to use.