Alignment data in patient-specific instrumented (PSI) knee arthroplasty have been examined in several meta-analyses, with demonstration of comparative but not improved restitution of a neutral mechanical axis and favorable outcomes in femoral implant axial alignment. To date, no comprehensive synthesis of data has been conducted specifically for functional outcomes. Relevant databases were searched according to Preferred Reporting Items for Systematic reviews and Meta-analyses guidelines during the period 2000 to 2015 of Levels 1 and 2 studies comparing functional outcomes of patient-specific instrumentation (PSI) versus conventional instrumentation. Outcomes of interest included postoperative Knee Society score (KSS) (function), KSS (knee), range of movement (ROM), Oxford knee scores (OKS), and Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores. Five randomized controlled trials and three prospective-comparative studies were included reporting on a total of 828 knees. All eight studies reported postoperative KSS (function) and seven studies reported KSS (knee). Three studies reported postoperative OKS, four documented ROM, and two reported WOMAC scores. Meta-analysis demonstrated equivalent KSS (function) scores 3 months postsurgery (Z = 1.71, p = 0.09). In addition, no significant differences were found for KSS (function) at 6 months (Z = 0.51, p = 0.61) or 12 to 24 months postsurgery (Z = 0.05, p = 0.96). In addition, no significant differences were found between PSI and conventional instrumentation for postoperative KSS (knee), ROM, or OKS. In summary, this systematic review and meta-analysis demonstrates no conclusive evidence for or against PSI when considering short-term functional outcomes. Further high-quality studies are required to investigate both mid- and long-term outcomes as well as survivorship data.