Background Idiopathic non-histaminergic acquired angioedema (InH-AAE) does not respond to anti-histamines and is possibly mediated by bradykinin. Objective To investigate the efficacy and safety of recombinant human C1-esterase inhibitor (rhC1-INH), for prophylaxis of InH-AAE, and to evaluate contact system parameters as biomarkers for attacks. Methods A prospective, open-label study of patients with InH-AAE with > 2 AE attacks/month. rhC1-INH (50 IU/kg was administered intravenously; maximum 4200 IU) twice weekly for 2 months, preceded and followed by a one-month period of observation. The primary endpoint was a >50% reduction in attack frequency. C1INH-function and plasma levels of high molecular weight kininogen, factor XII, plasma prekallikrein, C4, cleaved kininogen, d-dimer were evaluated as potential biomarkers. Post-trial follow-up was evaluated in all patients. Results Six patients (mean age 41 years; four female) were enrolled. One patient showed a reduction in attack frequency of 84% (3 versus 19) during rhC1-INH treatment, and showed clinical response to plasma-derived C1-INH but not to omalizumab post-trial. Restarting rhC1-INH treatment resulted in a similarly rapid response. The other 5 patients showed no improvement. No major adverse events were reported. None of the measured biomarkers were related to treatment response. Post-trial, omalizumab was administered to four patients, of which two reported response. Conclusion rhC1-INH treatment was effective in 1 of 6 InH-AAE patients, suggesting a bradykinin-dependent mechanism of attacks in this patient. Response to omalizumab or tranexamic acid during follow-up in a number of the patients points to a heterogeneous pathogenesis of InH-AAE disease requiring a personalised treatment approach.