Background: Cranioplasty is a reconstructive procedure to restore bone anatomy and repair skull defects. Optimum reconstruction could be a challenge for neurosurgeons, and therefore the strategy to attain the ideal result remains a subject of discussion. Aim: we aimed at comparing two completely different prostheses in reconstructing calvarial bone defects, titanium mesh and polymethyl methacrylate (PMMA) bone cement. We looked for the differences in the cosmetic and functional outcomes as well as the prosthesis-related complications. Patients and Methods: This was a randomized prospective study on the first forty successive adult patients with calvarial skull defects of different etiologies, sites and sizes admitted and operated upon at neurosurgery department, Minia University hospital between January 2017 and December 2018. We divided patients into 2 groups, Group1: 20 patients were operated upon using Titanium mesh and Group 2: 20 patients were operated upon using (PMMA) acrylic bone cement implants. Results: Regarding cosmetic appearance, functional outcome, and improvement of the clinical symptoms (syndrome of trephined), Cranioplasty using titanium mesh and acrylic bone cement proved to have non-significant differences in the reconstruction of calvarial skull defects of different etiologies. However, there is a statistically significant difference between both materials regarding complications especially with large skull defects (≥25 cm²). Conclusion: there is no statistical difference between both materials regarding cosmetic and functional outcomes. However, large bone defects (≥25 cm²)are better treated with titanium mesh due to lower incidence of complications.