Introduction: Anterior knee pain (AKP) may persist after total knee arthroplasty (TKA), even if well aligned and stable, and is reported in up to 30% of patients, leading to patient dissatisfaction. The gender-specific knee prostheses have been designed to reduce femoral component overhanging in females and improve patient satisfaction. The purpose of this study was to determine AKP between gender-specific knee prosthesis and unisex knee prosthesis following minimally invasive surgery (MIS) TKA with patellar resurfacing. Methods: This study was a randomized trial comparing a gender-specific vs. unisex knee prosthesis in females with knee osteoarthritis. Follow-up occurred at 6 weeks, 3 months, 6 months, 1 year, and 2 years. Pre- and postoperative AKP were measured at each follow-up. Intraoperative lateral overhanging of the femoral component and patellar tracking were also measured and compared between the two groups. Results: Sixty females were recruited; 30 underwent gender-specific knee prosthesis (Gp1) and 30 underwent unisex knee prosthesis (Gp2). No patients were lost to follow-up. The incidence rates of AKP and visual analog scale AKP pain scores at 2 years were 7 vs. 7% (p = 1.00) and 0.95 ± 0.31 (0–1) points vs. 1.10 ± 0.28 (0–1) points (p = 0.68) for gender and unisex prostheses, respectively. Patellar tilt and patellar shift were similar between the two groups. Patellar tilt and patellar shift were 2.56° ± 2.03 (0–8) vs. 2.67° ± 2.35 (0–9) (p = 0.46) and 1.25 ± 1.09 (0–3.2) mm vs. 1.15 ± 0.97 (0–2.9) mm (p = 0.34) for Gp1 and Gp2, respectively. Mean lateral femoral overhanging was 0.23 ± 0.63 mm (range: 1–2 mm, Gp1) vs. 1.57 ± 1.36 mm (range: 1–3 mm, Gp2) (p ≤ 0.001). Conclusion: Both types of prostheses had similar incidence rates of AKP, VAS scores for AKP. Lateral femoral overhanging of ≤ 3 mm was not the cause of AKP.