The goal of this study was to report the clinical outcomes of pathologic humeral shaft fractures treated with reamed or unreamed intramedullary nail fixation in an era of longer patient survival. A retrospective review was conducted of all patients who underwent intramedullary nail fixation performed by a single surgeon for pathologic humeral shaft fractures at a Level I trauma center from 2009 to 2017. Of the 25 patients who were identified, 9 were excluded. Groups were categorized according to whether they underwent reamed or unreamed fixation, and they were evaluated for evidence of union, complications, and reoperation. Of the patients, 11 underwent an unreamed procedure and 5 underwent a reamed procedure. Mean length of follow-up was 51.5 weeks. Of the patients who participated, 12 (75%) showed evidence of union and 2 patients (12.5%) showed evidence of nonunion, with no statistical difference between the groups. Five patients (31.3%) had complications. One nonunion occurred in the reamed group and did not require reoperation. In the unreamed group, complications consisted of 1 delayed union, 1 nonunion treated with revision intramedullary nail fixation, and 2 cases of disease progression that required reoperation. Intramedullary nail fixation of pathologic humeral shaft fractures achieves rates of union parallel to those seen with fixation in a healthy population. The length of follow-up in the current study was longer than the life expectancy reported by previous authors, which can be attributed to improvements in the treatment of cancer. The current authors argue that unreamed fixation is the optimal technique because it yields similar outcomes to a reamed approach and is faster and potentially safer. [Orthopedics. 2020;43(5):e389-e398.].