Background There is a lack of consensus regarding optimal surgical management of displaced and unstable three-part proximal humeral fractures. Questions/purposes The objective of this prospective observational study was to compare the clinical and radiologic outcomes of plate versus nail fixation of threepart proximal humeral fractures. Patients and Methods Two hundred eleven patients with unstable three-part proximal humeral fractures were treated with ORIF using plate (PHILOS [proximal humeral interlocking system]/LPHP [locking proximal humerus plate]) or nail (PHN [proximal humeral nail]) osteosynthesis. Outcome measurements included pain, Constant and Murley and Neer scores, and the occurrence of complications at 3, 6, and 12 months postsurgery. Regression analysis and the likelihood ratio test were used to evaluate differences between the cohorts.