Background <p>Isolated medial patellofemoral ligament (MPFL) reconstruction is an effective, low-morbidity treatment for recurrent lateral patellofemoral instability (RLPI). The presence of major anatomical risk factors continues to generate controversy in surgical decision-making. It remains unclear whether the coexistence of multiple risk factors requires associated bony procedures or whether isolated MPFL reconstruction alone is sufficient. The purpose of this prospective study was to compare clinical outcomes, recurrence rates, return to sport, and patellofemoral degenerative changes in athletes with RLPI presenting with ≤ 1 versus 1 associated majorrisk factor treated with isolated MPFL reconstruction.</p> Methods <p>This prospective cohort study included athletes aged 16–30 years with RLPI who underwent isolated MPFL reconstruction between 2013 and 2020. Patients were stratified according to the number of associated major risk factors (MRFs): ≤ 1 MRF (group 1) and 1 MRF (group 2). MRFs included trochlear dysplasia, patella alta, increased tibial tuberosity–trochlear groove distance, increased femoral anteversion, and increased tibial torsion. All patients underwent isolated MPFL reconstruction using the same surgical technique. Functional outcomes were assessed using the Knee injury and Osteoarthritis Outcome Score (KOOS), Kujala score, International Knee Documentation Committee (IKDC) score, and Lysholm score. Recurrence of instability, return to sport (RTS), and patellofemoral degenerative changes were evaluated. Minimum follow-up was 5 years.</p> Results <p>A total of 86 athletes (43 per group) completed a minimum 5-year follow-up. Both groups showed significant postoperative improvements in all functional scores. At final follow-up, no between-group differences were observed (KOOS QoL mean difference 2.1; Kujala 0.8; IKDC 1.2; Lysholm 1.5; all <i>p</i> 0.05). MCID and PASS achievement rates were comparable between groups. Recurrence occurred in one patient per group (2.3%). More than 90% of athletes returned to sport at their preinjury level within 1 year. Mild, asymptomatic patellofemoral degenerative changes were observed in a small proportion of patients, with no between-group differences.</p> Conclusions <p>With a medium-term follow-up, isolated MPFL reconstruction appeared to be a reliable and effective surgical option for treating RLPI in athletes from both groups. The procedure was associated with significant improvements in both primary and secondary outcomes and remained effective regardless of the number or type of associated major risk factors.</p> Level of evidence <p>II, prospective cohort study.</p>