The present study was conducted to investigate and compare effectiveness of preoperative Acetaminophen and Rofecoxib for treatment of pain associated with orthodontic separator placement. The 45 subjects were randomly divided into three groups. Each group of the study included 15 patients. Subjects in each of these 3 groups were assigned to the following 1) Group A: 15 patients took 500 mg of Acetaminophen (Paracip 500 mg, Cipla) orally 1 hour before separator placement and a lactose placebo orally 1 hour after separator placement. 2) Group B: 15 patients took 25 mg of Rofecoxib (Rofica 25 mg Microlabs Ltd.) orally 1 hr before separator placement and a lactose placebo orally 1 hr after separator placement. 3) Group C (Control group): 15 subjects took lactose placebo tablets (custom made) orally 1 hr before separator placement and 1 hr after separator placement. In the above three groups, the patient''s pain threshold was assessed by using Visual Analogue Scales (VAS) while performing the following activities; chewing, biting, fitting back teeth, and fitting front teeth together. The finding were statistically analyzed.