Grapefruit (Citrus Paradise, family Rutaceae) is a citrus fruit that is low in calories and rich in dietary fibers. Sibutramine (Sibutramine hydrochloride monohydrate) is an anti-obesity drug that enhances satiety. The effect of grapefruit juice and sibutramine on body weight and neurotransmitters controlling appetite was investigated in obese rats. Rats were assigned to two dietary groups for 3 weeks; control group (n=6) was fed commercial standard pellets diet and obese group (n=24) was fed cafeteria diet (hypercaloric diet consisting of highly palatable food). The effect of sibutramine and grapefruit juice was studied on obese rats. Statistical difference and interactions were evaluated through one-way analysis of variance test (one-way ANOVA) followed by Dunnett's test was used for means of different groups. For all statistical tests done, a 0.05 level of probability was used as the criterion for significance. Grapefruit juice produced its weight reduction effect after 1 week of administration and lasted till the end of the experiment and did not affect brain neurotransmitters. Sibutramine produced its weight reduction effect after 1 week of administration and lasted for only 2 weeks and produced an increase in brain noradrenaline while grapefruit juice produced its effect from the first week till the end of the study. It can be concluded that grapefruit juice is better than sibutramine since its effect lasted till the end of the experiment and also did not affect brain noradrenaline.