Purpose Previous clinical trials suggested that inhaled nitric oxide (iNO) could have beneficial effects in sickle cell disease (SCD) patients with acute chest syndrome (ACS). Methods To determine whether iNO reduces treatment failure rate in adult patients with ACS, we conducted a prospective, double-blind, randomized, placebo-controlled clinical trial. iNO (80 ppm, N  = 50) gas or inhaled nitrogen placebo ( N  = 50) was delivered for 3 days. The primary end point was the number of patients with treatment failure at day 3, defined as any one of the following: (1) death from any cause, (2) need for endotracheal intubation, (3) decrease of PaO 2 /FiO 2  ≥ 15 mmHg between days 1 and 3, (4) augmented therapy defined as new transfusion or phlebotomy. Results The two groups did not differ in age, gender, genotype, or baseline characteristics and biological parameters. iNO was well tolerated, although a transient decrease in nitric oxide concentration was mandated in one patient. There was no significant difference in the primary end point between the iNO and placebo groups 23 (46 %) and 29 (58 %); odds ratio (OR), 0.8; 95 % CI, 0.54–1.16; p  = 0.23. A post hoc analysis of the 45 patients with hypoxemia showed that those in the iNO group were less likely to experience treatment failure at day 3 7 (33.3 %) vs 18 (72 %); OR = 0.19; 95 % CI, 0.06–0.68; p  = 0.009. Conclusions iNO did not reduce the rate of treatment failure in adult SCD patients with mild to moderate ACS. Future trials should target more severely ill ACS patients with hypoxemia. Clinical trial registration NCT00748423.