Abstract Context Episodic breathlessness is common and debilitating in cancer patients. Objectives In this pilot study, we examined the effect of prophylactic fentanyl pectin nasal spray (FPNS) on exercise-induced dyspnea, physiologic function and adverse events. Methods In this parallel, double-blind randomized placebo-controlled trial, opioid-tolerant patients performed three six-minute walk tests (6MWT) to induce dyspnea. They were randomized to receive either FPNS (15-25% of total daily opioid dose each time) or placebo 20 minutes before the second and third 6MWTs. We compared dyspnea numeric rating scale (NRS, 0-10, primary outcome), walk distance, vital signs, neurocognitive function and adverse events between the first and second 6MWTs (T2-T1) and between the first and third 6MWTs (T3-T1). Results Twenty-four patients enrolled, with 96% completion. FPNS was associated with significant within-arm reduction in dyspnea NRS at rest (T2-T1: -0.9 95% confidence interval CI -1.7,-0.1; T3-T1: -1.3 95% CI -2.0,-0.5) and after six minutes (T2-T1: -2.0 95% CI -3.5,-0.6; T3-T1: -2.3 95% CI -4.0,-0.7), and longer walk distance (T2-T1 +23.8m 95% CI +1.3,+46.2m; T3-T1: +23.3m 95% CI -1.7,+48.2). In the placebo arm, we observed no significant change in walk distance nor dyspnea NRS at rest, but significant reduction in dyspnea NRS at 6 minutes (T2-T1: -1.7 95% CI -3.3,-0.1; T3-T1: -2.5 95% CI -4.2,-0.9). Vital signs, neurocognitive function and adverse effects did not differ significantly. Conclusion FPNS was safe, reduced dyspnea at rest and increased walk distance in before-after comparison. The placebo effect was substantial, which needs to be factored in future study designs.( clinicaltrials.gov registration: NCT01832402)