© 2014, National Research Council of Canada. All rights reserved.Vascular bubble formation results from supersaturation during inadequate decompression contributes to endothelial injuries, which form the basis for the development of decompression sickness (DCS). Risk factors for DCS include increased age, weight–fat mass, decreased maximal oxygen uptake, chronic diseases, dehydration, and nitric oxide (NO) bioavailability. Production of NO is often affected by diving and its expression–activity varies between the genders. Little is known about the influence of sex on the risk of DCS. To study this relationship we used an animal model of N?-nitro-L-arginine methyl ester (L-NAME) to induce decreased NO production. Male and female rats with diverse ages and weights were divided into 2 groups: treated with L-NAME (in tap water; 0.05 mg·mL–1 for 7 days) and a control group. To control the distribution of nitrogen among tissues, 2 different compression–decompression protocols were used. Results showed that L-NAME was significantly associated with increased DCS in female rats (p = 0.039) only. Weight was significant for both sexes (p = 0.01). The protocol with the highest estimated tissue pressures in the slower compartments was 2.6 times more likely to produce DCS than the protocol with the highest estimated tissue pressures in faster compartments. The outcome of this study had significantly different susceptibility to DCS after L-NAME treatment between the sexes, while L-NAME per se had no effect on the likelihood of DCS. The analysis also showed that for the appearance of DCS, the most significant factors were type of protocol and weight.