The aim of this randomized controlled triple blind trial was to compare the efficacy of clonidine with dexamethasone versus ondansetron with dexamethasone for postoperative pain, nausea and vomiting prevention in orthognathic surgery patients. In this clinical trial study, 30 consecutive patients with skeletal class III deformities were candidates for orthognathic surgery in Qaem hospital, Mashhad University of medical sciences, Mashhad, Iran from March to November 2017. These subjects were randomly assigned to two equal number groups, ondansetron or clonidine. Patients received either oral ondansetron 8mg or oral clonidine 150?g as premedication, 1 hour before the surgery (both dissolved in 20 cc of water). Also both groups received intravenous dexamethasone 8mg (1 hour preoperatively and every 4 hours intraoperatively). In this study, a total of 30 patients (14 males and 16 females) with a mean age of 23.9 ± 3.9 were investigated. The incidence of postoperative nausea in women was more than men (p=0.003), also the correlation between the incidence of PON and the surgery duration ? 3 hours was statistically significant (p = 0.050). The frequency of postoperative nausea (PON) in the ondansetron group was less than clonidine (53.3% vs 73.3% respectively). There was no postoperative vomiting (POV) in the ondansetron group, but 6.7% of cases in clonidine group suffered POV. Post-operative nausea in ondansetron group occurred significantly later than clonidine (525.0±233.2 vs 100.0±34.0 min; p<0.001). On the other hand, the incidence time of post-operative severe pain or in other word the analgesia time in clonidine group was significantly more than ondansetron one (875/0±68/5 vs 614.3±159.1 min; p<0.001). Ondansetron with dexamethasone premedication was more effective in controlling PONV after orthognathic surgery compared to clonidine with dexamethasone group.