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The purpose of this study was to determine the effect of tibiofemoral alignment, femoral and tibial component alignment, and body-mass index (BMI) on implant survival following total knee replacement.We retrospectively reviewed 6070 knees in 3992 patients with a minimum of two years of follow-up. Each knee was classified on the basis of postoperative alignment (overall tibiofemoral alignment and alignment of the tibial and the femoral component in the coronal plane). Failures (defined as revision for any reason other than infection) were analyzed with use of Cox regression; patient covariates included overall alignment, component alignments, and preoperative BMI.Failure was most likely to occur if the orientation of the tibial component was <90° relative to the tibial axis and the orientation of the femoral component was ≥8° of valgus (failure rate, 8.7%; p < 0.0001). In contrast, failure was least likely to occur if both the tibial and the femoral component were in a neutral orientation (≥90° and <8° of valgus, respectively) (failure rate, 0.2% [nine of 4633]; p < 0.0001). “Correction” of varus or valgus malalignment of the first implanted component by placement of the second component to attain neutral tibiofemoral alignment was associated with a failure rate of 3.2% (p = 0.4922) for varus tibial malalignment and 7.8% (p = 0.0082) for valgus femoral malalignment. A higher BMI was associated with an increased failure rate. Compared with patients with a BMI of 23 to 26 kg/m2, the failure rate in patients with a BMI of ≥41 kg/m2 increased from 0.7% to 2.6% (p = 0.0046) in well-aligned knees, from 1.6% to 2.9% (p = 0.0180) in varus knees, and from 1.0% to 7.1% (p = 0.0260) in valgus knees.Attaining neutrality in all three alignments is important in maximizing total knee implant survival. Substantial “correction” of the alignment of one component in order to compensate for malalignment of the other component and thus produce a neutrally aligned total knee replacement can increase the risk of failure (p = 0.0082). The use of conventional guides to align a total knee replacement provides acceptable alignment; however, the surgeon should be aware that the patient's size, as determined by the BMI, is also a major factor in total knee replacement failure.Prognostic Level II. See Instructions to Authors for a complete description of levels of evidence.