A method to maintain organ blood flow during laparoscopic surgery has not been developed. Here we determined if ethyl nitrite, an S‐nitrosylating agent that would maintain nitric oxide bioactivity (the major regulator of tissue perfusion), might be an effective intervention to preserve physiologic status during prolonged pneumoperitoneum. The study was conducted on appropriately anesthetized adult swine; the period of pneumoperitoneum was 240 minutes. Cohorts consisted of an anesthesia control group and groups insufflated with CO₂ alone or CO₂ containing fixed amounts of ethyl nitrite (1–300 ppm). Insufflation with CO₂ alone produced declines in splanchnic organ blood flows and it reduced circulating levels of S‐nitrosohemoglobin (i.e., nitric oxide bioactivity); these reductions were obviated by ethyl nitrite. In a specific example, preservation of kidney blood flow with ethyl nitrite kept serum creatinine and blood urea nitrogen concentrations constant whereas in the CO₂ alone group both increased as kidney blood flow declined. The data indicate ethyl nitrite can effectively attenuate insufflation‐induced decreases in organ blood flow and nitric oxide bioactivity leading to reductions in markers of acute tissue injury. This simple intervention provides a method for controlling a major source of laparoscopic‐related morbidity and mortality: tissue ischemia and altered postoperative organ function.