Objective: Fatal allergic responses and cardiac arrhythmias have been reported with the intravenous (IV) administration of polidocanol. We sought to identify the physiologic mechanism of systemic cardiovascular response after transcervical (TC) and IV administration of polidocanol. Methods: We continuously monitored blood pressure (BP) and heart rate using an arterial line during IV and intraperitoneal (IP) administration of polidocanol solution (PS) and polidocanol doxycycline solution in female rats and TC and IP administration of polidocanol foam (PF) and PDF (TC only) in female baboons. We performed TC procedures using a catheter with (pressurized) and without (nonpressurized) balloon inflation. Baboons also underwent monitoring during IV PS administration with and without pretreatment with antihistamines. We performed cardiac echo and electrocardiograms during selected experiments. We defined a refractory hypotension as a sustained decrease of more than 30% from baseline that prevented delivery of the target dose. Results: We found a dose-related increase in the proportion of baboons that developed refractory hypotension during TC administration of 5% PDF and PF, an effect confined to pressurized administration. The infusion of 0.5% PS in rats induced a rapid and dramatic refractory hypotension. The inclusion of doxycycline did not improve or deteriorate these outcomes, and doxycycline solution or saline (control) alone did not affect BP. All five female baboons that received up to 20 mL of 1% PS (200 mg) developed refractory hypotension. Pretreatment with diphenhydramine, ranitidine, or both did not block the refractory hypotension induced by IV administration of 1% PS (100 mg). In contrast, only one of the six female baboons treated with IP PF 400 mg developed a decrease of more than 30% in BP, and this response was not sustained. Cardiac echocardiography done in four baboons during TC treatment demonstrated a decrease in cardiac output as the physiologic mechanism of hypotension. We did not observe important changes on the electrocardiograms. Conclusions: Adverse cardiovascular effects of polidocanol treatment occur owing to a direct myocardial effect of polidocanol and not as a result of a hypersensitivity reaction. Pressurized TC administration of PF results in refractory hypotension owing to endometrial vascular uptake of polidocanol and not as a result of uptake from peritoneal surfaces.