Obtaining adequate sacral fixation is an important and challenging clinical problem. Bicortical screw fixation has been used to provide improved mechanical strength. The goal of this study was to evaluate the effects of depth of penetration (unicortical versus bicortical), orientation (medial versus lateral), and bone density on the strength of the bone-screw interface. Seven-millimeter Steffee screws (Acromed, Cleveland, Ohio) were placed in human cadaveric sacra. The screws were placed either medially into the centrum of the S1 body or laterally into the sacral ala. The fixation systems used, either bicortical or unicortical, were tested on a Universal testing machine. The specimens were loaded to failure and biomechanical parameters were measured. Medially oriented screws sustained the highest load to failure. In an older population, unicortical fixation sustained load to failure and initial compliance findings were similar to those for bicortical fixation. The regional bone density in the centrum of the first sacral body was denser than that in the lateral alar region, and also provided more rigid bone screw fixation.