Background Patient-specific cutting blocks have been touted as a more efficient and reliable means of achieving neutral mechanical alignment during TKA with the proposed downstream effect of improved clinical outcomes. However, it is not clear to what degree published studies support these assumptions. Questions/purposes We asked: (1) Do patient-specific cutting blocks achieve neutral mechanical alignment more reliably during TKA when compared with conventional methods? (2) Does patient-specific instrumentation (PSI) provide financial benefit through improved surgical efficiency? (3) Does the use of patient-specific cutting blocks translate to improved clinical results after TKA when compared with conventional instrumentation? Methods We performed a systematic review in accordance with Cochrane guidelines of controlled studies (prospective and retrospective) in MEDLINE 1 and EM-BASE 1 with respect to patient-specific cutting blocks and their effect on alignment, cost, operative time, clinical outcome scores, complications, and survivorship. Sixteen studies (Level I-III on the levels of evidence rubric) were identified and used in addressing the first question, 13 (Level I-III) for the second question, and two (Level III) for the third question. Qualitative assessment of the selected Level I studies was performed using the modified Jadad score; Level II and III studies were rated based on the Newcastle-Ottawa scoring system. Results The majority of studies did not show an improvement in overall limb alignment when PSI was compared with standard instrumentation. Mixed results were seen across studies with regard to the prevalence of alignment outliers when PSI was compared with conventional cutting blocks with some studies demonstrating no difference, some showing an improvement with PSI, and a single study showing worse results with PSI. The studies demonstrated mixed results regarding the influence of PSI on operative times. Decreased operative times were not uniformly observed, and when noted, they were found to be of minimal clinical or financial significance. PSI did reliably reduce the number of instrument trays required for processing perioperatively. The accuracy of the preoperative plan, generated by the PSI manufacturers, was found lacking, often leading to multiple intraoperative changes, thereby disrupting the flow of the operation and negatively impacting efficiency. Limited data exist with regard to the effect of PSI on postoperative function, improvement in pain, and patient