Titanium plates and screws (TPS) are the current standard of care for fixation of cranial bone flaps. These materials have been used for decades but have known potential complications, including flap migration, bone resorption/incomplete osseous union, hardware protrusion, cosmetic deformity, wound infection/dehiscence, and cerebrospinal fluid (CSF) leakage. This study evaluated the efficacy of a novel mineral-organic bone adhesive (Tetranite) for cranial bone flap fixation. Craniotomy bone flaps created in human cadaveric skulls were tested under quasistatic and impact loading in the following conditions: 1) uncut skull; 2) bone flaps fixated with TPS alone; and 3) bone flaps fixated with bone adhesive alone. All fixative surgical procedures were performed by a group of 16 neurosurgeons in a simulated surgical environment. The position of adhesive-fixated cranial bone flaps was measured using computed tomography and compared with their original native location. The resistance of adhesive-fixated cranial bone flaps to simulated CSF leakage was also evaluated. Because there was a gap around the circumference of the TPS-fixated specimens that was visible to the naked eye, pressurized CSF leak testing was not attempted on them. Adhesive-fixated bone flaps showed significantly stiffer and stronger quasistatic responses than TPS-fixated specimens. The strength and stiffness of the adhesive-fixated specimens were not significantly different from those of the uncut native skulls. Total and plastic deflections under 6-J impact were significantly less for adhesive-fixed bone flaps than TPS. There were no significant differences in any subthreshold impact metrics between the adhesive-fixed and native specimens at both 6-J and 12-J impact levels, with 1 exception. Plastic deflection at 6-J impact was significantly less in adhesive-fixated bone flaps than in native specimens. The energy to failure of the adhesive-fixated specimens was not significantly different from that of the native specimens. Time since fixation (20 minutes vs 10 days) did not significantly affect the impact failure properties of the adhesive-fixated specimens. Of the 16 adhesive-fixated craniotomy specimens tested, 14 did not leak at pressures as high as 40 mm Hg. The neurosurgeons in this study had no prior exposure or experience with the bone adhesive. Despite this, improved resistance to CSF egress, superior mechanical properties, and better cosmetic outcomes were demonstrated with bone adhesive compared with TPS.