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The purpose of this systematic review and meta-analysis is to compare patient-specific instrumentation (PSI) versus standard instrumentation for total knee arthroplasty (TKA) with regard to coronal and sagittal alignment, operative time, intraoperative blood loss, and cost. A systematic query in search of relevant studies was performed, and the data published in these studies were extracted and aggregated. In regard to coronal alignment, PSI demonstrated improved accuracy in femorotibial angle (FTA) (P = 0.0003), while standard instrumentation demonstrated improved accuracy in hip-knee-ankle angle (HKA) (P = 0.02). Importantly, there were no differences between treatment groups in the percentages of FTA or HKA outliers (>3 degrees from target alignment) (P = 0.7). Sagittal alignment, operative time, intraoperative blood loss, and cost were also similar between groups (P > 0.1 for all comparisons).