Background Custom cutting guides (CCGs; sometimes called patient-specific instrumentation [PSI]) in total knee arthroplasty (TKA) use preoperative three-dimensional imaging to fabricate cutting blocks specific to a patient's native anatomy. Questions/purposes The purposes of this study were to determine if CCGs (1) improve clinical outcomes as measured by UCLA activity, SF-12, and Oxford knee scores; and (2) coronal mechanical alignment versus standard alignment guides. Methods This was a retrospective cohort study of patients undergoing primary TKA using the same cruciate-retaining, cemented TKA system between January 2009 and April 2012. Patients were included if they were candidates for a unilateral, cruciate-retaining TKA and met other prespecified criteria; patients were allowed to self-select either an MRI-based CCG procedure or standard TKA. Ninety-seven of 120 (80.8%) patients in the standard and 104 of 124 (83.9%, p = 0.5) in the CCG cohort with a minimum of 1-year followup were available for analysis. The first 95 patients in the standard (mean followup, 3 years; range, 1-4 years) and CCG (mean followup, 2 years; range, 1-4 years) cohorts were compared. The alignment goal for all TKAs was a hip-knee-ankle (HKA) angle of 0°. UCLA, SF-12, and Oxford knee scores were collected preoperatively and at each patient's most recent followup visit. Postoperative, rotationally controlled coronal scout CT scans were used to measure HKA alignment. Independent-sample t-tests and chi-square tests were used