Background: Zimmer iASSIST knee is an accelerometer-based navigation system with the aim of achieving better alignment in total knee arthroplasty (TKA). We have started using this system since early 2016. This is a retrospective case–control study, which aims to compare the radiological alignment, operation time, and blood loss of TKAs performed using the iASSIST system and those using conventional techniques. Materials and Methods: 42 TKAs using Zimmer iASSIST and 44 TKAs using conventional instrumentation were recruited. The overall coronal alignment and the coronal and sagittal alignment of the femoral and tibial component were compared. For coronal alignment, additional analysis of the absolute deviation from neutral mechanical axis was performed to avoid canceling out of varus/valgus deviation. The number of outliers, operation time, and blood loss in terms of maximal hemoglobin drop were also compared. Results: When comparing the alignment of the iASSIST group with the conventional group, there were no significant differences ( p > 0.05) in the number of outliers, mean coronal alignments, mean deviation from neutral coronal mechanical axis (2.9° vs. 2.9°), and femoral component flexion angle (4.9° vs. 4.7°). The difference in the mean tibial component posterior slope was significant (5.7° vs. 7.1°, p < 0.05). The mean operation time was significantly longer by 13 min ( p < 0.05) in the iASSIST group. There were no significant differences in the mean hemoglobin drop between the two groups. Conclusion: The results demonstrated no significant differences in terms of coronal radiological alignment, femoral flexion angle, outliers, and blood loss between iASSIST and conventional technique. There was a small but statistically significant difference in tibial posterior slope. The iASSIST group needed a longer operation time.