This study was performed to determine the effect of cold application and heparinoid cream on periorbital edema and ecchymosis after craniotomy. The sample of this prospective parallel-arm, randomized controlled trial included 90 neurosurgical patients who underwent anterior craniotomy in two medical faculty hospitals of a university in Turkey. The patients were randomly assigned (1:1:1) to the cold application, heparinoid or control groups. Those patients in the cold application group received cold application with gel pack on their periorbital areas for 20 minutes per hour for three days beginning from the 3rd hour following craniotomy. On the other hand, the patients in the heparinoid group received heparinoid cream on their periorbital areas once at the 3rd and 9th hours after craniotomy and then four times/day at 6-hour intervals for three postoperative days. Periorbital edema and ecchymosis were evaluated for three days after craniotomy using Kara & Gokalan’s scale by blinded observers. In all the measurements after craniotomy, except for those at the 3rd hour, the periorbital edema score of the cold application group was significantly lower than those of both the heparinoid and control groups (p<0.001). The upper and lower eyelid ecchymosis scores of the cold application group were significantly lower than those of both the heparinoid and control groups on the 1st, 2nd and 3rd days after craniotomy (p<0.001). In the cold application group, periorbital edema score decreased significantly as the skin temperature decreased only on the 3rd day after craniotomy (p=0.01). The study revealed that cold application and heparinoid cream administered for three days beginning from the 3rd hour after craniotomy did not prevent postoperative periorbital edema and ecchymosis, but cold application significantly reduced periorbital edema and ecchymosis.