Forty-three randomized controlled trials including 3,703 patients with primary total knee arthroplasty were included in this systematic review and meta-analysis comparing patient-specific instrumentation (PSI) vs. non-PSI. Pooled outcomes of interest included patient-reported outcome measures (PROMS), clinical outcome scores, peri-operative blood loss, revision rates, and complication rates. The results indicated no clinically relevant differences in efficacy or safety between the PSI and non-PSI groups. There was considerable heterogeneity, with earlier studies showing a positive effect for PSI, while later studies showed the opposite. The study concludes that PSI does not provide clinically significant benefits over conventional instrumentation in primary TKA.