The objectives of this study were (1) to determine the most advantageous screw locations within the humeral head when plate and screw fixation is to be used and (2) to determine the effect of positioning the screw tip abutting the subchondral bone. Ten paired humeral heads were harvested with a monoplanar cut through the anatomic neck. Through use of a standardized template, 7 holes were drilled and tapped in each specimen for insertion of 6.5-mm fully threaded cancellous screws perpendicular to the plane of the cut. Paired specimens were randomized into 2 groups, one with the screw purchase in central cancellous bone and the other with the screw purchase up to the subchondral bone. Each screw was pulled out axially at a displacement rate of 10 mm/min through use of a servohydraulic testing machine. The length of thread purchase, position within the head, and screw pull-out load to failure were recorded. The normalized pullout force to failure was calculated by dividing absolute pullout force to failure by length of screw purchase. Data were analyzed by means of a 2-way repeated measures analysis of variance and post hoc Student-Newman-Keuls test. The central position had a significantly higher absolute pullout force to failure than all other sites (P < .05). By virtue of the humeral head shape, the central position also had a significantly greater length of screw purchase than all other positions (P < .05). The central position had a significantly higher relative pullout force to failure than all other positions (P < .05). Subchondral bone abutment positioning improved both the absolute and the relative pullout forces to failure (P < .05). When screws and plates are used in open reduction and internal fixation of a proximal humerus fracture, a major mode of failure is loss of fixation within the humeral head. On the basis of this study, optimal screw purchase with respect to bone fixation can be achieved by including screws located in the center of the humeral head in the subchondral abutment position. To minimize screw fixation failure, the anterosuperior position should be avoided. The pattern of distribution of the relative pullout force as measured in this study is consistent with previous observational studies of patterns of trabecular density within the humeral head.