Antegrade femoral nailing through a piriformis fossa starting point in patients who are obese has been demonstrated to be problematic. Retrograde femoral nailing therefore has been advocated in this patient population, but little data exist to support such a recommendation. The purpose of this study was to evaluate and compare antegrade and retrograde femoral nailing technique in both patients who are and are not obese. Prospective, multicenter, nonrandomized, internal review board (IRB)-approved study. Four Level 1 trauma centers. Patients (151) with a femoral shaft fracture (OTA 32) treated with intramedullary nailing were studied. Thirty-two with a body mass index (BMI) of >or=30 comprised the obese group (OG), and 119 with a BMI of <30 comprised the nonobese group (NOG). Antegrade nailing was performed in 15 patients from the OG and 84 from the NOG. Retrograde nailing was performed in 17 patients from the OG and 35 from the NOG. Reamed intramedullary nailing of a femoral shaft fracture. Patient and fracture characteristics, operative time, fluoroscopy time, healing, complications, and functional outcome based on the lower extremity measure (LEM) were evaluated. Antegrade technique in the OG was associated with a 52% greater average operative time (94 minutes) compared with antegrade nailing in the NOG (62 minutes; P < 0.003). For retrograde nailing technique, there was no difference in the average operative time between the OG (67 minutes) and NOG (62 minutes; P = 0.51). Antegrade technique in the OG was associated with a 79% greater average radiation exposure time (247 seconds) compared with antegrade nailing in the NOG (135 seconds; P < 0.03). For retrograde nailing technique, average fluoroscopy time was similar between the OG (76 seconds) and the NOG (63 seconds; P = 0.44). Within the OG, antegrade nailing required 40% greater average operative time (94 minutes versus 67 minutes, P < 0.02) and more than 3 times more average fluoroscopy time (242 seconds versus 76 seconds, P < 0.002) than retrograde nailing. Thirty-eight patients from the original cohort were not available for follow-up. Of the 113 patients followed (average 9 months, range: 4 to 25 months), healing complications occurred similarly between the 2 groups, with 1 nonunion and 2 delayed unions in the OG (12%), and 3 nonunions and 9 delayed unions in the NOG (14%). This study provides evidence, in the form of decreased operative and radiation exposure times, to support the use of retrograde nailing technique for the treatment of femoral shaft fractures in patients who are obese. Also, antegrade nailing was found to require significantly more operative and radiation exposure time in the patient who is obese as opposed to the patients who is not obese. Although having similar baseline functional scores, patients who are obese recovered at a slower rate and more incompletely than patients who are not obese.