Exercise-induced fatigue reduces muscle force production and motoneuron pool excitability. However, it is unclear if patients with patellofemoral pain (PFP) experience further loss in quadriceps neuromuscular function due to fatigue during exercise and postexercise. To observe how quadriceps maximal strength, activation, and force-generating capacity change during and after repetitive bouts of isokinetic knee-extension exercise in patients with PFP. Cross-sectional study. Laboratory. Twenty-two patients with PFP (visual analog scale mean pain severity = 4.2 of 10 cm, mean symptom duration = 38.6 months) and 19 healthy control individuals matched on age and body mass index. Quadriceps peak torque (PT), central activation ratio (CAR), and rate of torque development (RTD) were assessed at baseline and immediately after every 5 sets of knee-extension exercise (times 1-5). Participants continued knee-extension exercises until the baseline quadriceps PT dropped below 50% for 3 consecutive contractions. No group-by-time interaction was observed for quadriceps PT (F5,195 = 1.03, P = .40). However, group-by-time interactions were detected for quadriceps CAR (F5,195 = 2.63, P= .03) and RTD (F5,195 = 3.85, P = .002). Quadriceps CAR (-3.6%, P = .04, Cohen d = 0.53) and RTD (-18.9%, P = .0008, Cohen d = 1.02) decreased between baseline and time 1 in patients with PFP but not in their healthy counterparts (CAR -1.9%, P = .86; RTD -9.8%, P = .22). Quadriceps RTD also decreased between times 4 and 5 in patients with PFP (-24.9%, P = .002, Cohen d = 0.89) but not in the healthy group (-0.9%, P = .99). Patients with PFP appeared to experience an additional reduction in quadriceps activation, force-generating capacity, or both during the early and late stages of exercise compared with healthy individuals. Clinicians should be aware of such possible acute changes during exercise and postexercise and use fatigue-resistant rehabilitation programs for patients with PFP.