Context: Noncontact anterior cruciate ligament injury has been reported to occur during the later stages of a game when fatigue is most likely present. Few researchers have focused on progressive changes in lower extremity biomechanics that occur throughout fatiguing. Objective: To evaluate the effects of a sequential fatigue protocol on lower extremity biomechanics during a sidestep-cutting task (SS). Design: Controlled laboratory study. Setting: Laboratory. Patients or Other Participants: Eighteen uninjured female collegiate soccer players (age = 19.2 +/- 0.9 years, height = 1.66 +/- 0.5 m, mass = 61.6 +/- 5.1 kg) volunteered. Intervention(s): The independent variable was fatigue level, with 3 levels (prefatigue, 50% fatigue, and 100% fatigue). Using 3-dimensional motion capture, we assessed lower extremity biomechanics during the SS. Participants alternated between a fatigue protocol that solicited different muscle groups and mimicked actual sport situations and unanticipated SS trials. The process was repeated until fatigue was attained. Main Outcome Measure(s): Dependent variables were hip- and knee-flexion and abduction angles and internal moments measured at initial contact and peak stance and defined as measures obtained between 0% and 50% of stance phase. Results: Knee-flexion angle decreased from prefatigue (-17 degrees +/- 5 degrees ) to 50% fatigue (-16 degrees +/- 6 degrees ) and to 100% fatigue (-14 degrees +/- 4 degrees ) (F2,34 = 5.112, P = .004). Knee flexion at peak stance increased from prefatigue (-52.9 degrees +/- 5.6 degrees ) to 50% fatigue (-56.1 degrees +/- 7.2 degrees ) but decreased from 50% to 100% fatigue (-50.5 degrees +/- 7.1 degrees ) (F2,34 = 8.282, P = 001). Knee-adduction moment at peak stance increased from prefatigue (0.49 +/- 0.23 Nm/kgm) to 50% fatigue (0.55 +/- 0.25 Nm/kgm) but decreased from 50% to 100% fatigue (0.37 +/- 0.24) (F2,34 = 3.755, P = 03). Hip-flexion angle increased from prefatigue (45.4 degrees +/- 10.9 degrees ) to 50% fatigue (46.2 degrees +/- 11.2 degrees ) but decreased from 50% to 100% fatigue (40.9 degrees +/- 11.3 degrees ) (F2,34 = 6.542, P = .004). Hip flexion at peak stance increased from prefatigue (49.8 degrees +/- 9.9 degrees ) to 50% fatigue (52.9 degrees +/- 12.1 degrees ) but decreased from 50% to 100% fatigue (46.3 degrees +/- 12.9 degrees ) (F2,34 = 8.639, P = 001). Hip-abduction angle at initial contact decreased from prefatigue (-13.8 degrees +/- 6.6 degrees ) to 50% fatigue (-9.1 degrees +/- 6.5 degrees ) and to 100% fatigue (-7.8 degrees +/- 6.5 degrees ) (F2,34 = 11.228, P $<$ .001). Hip-adduction moment decreased from prefatigue (0.14 +/- 0.13 Nm/kgm) to 50% fatigue (0.08 +/- 0.13 Nm/kgm) and to 100% fatigue (0.06 +/- 0.05 Nm/kg) (F2,34 = 5.767, P = .007). Conclusions: The detrimental effects of fatigue on sagittal and frontal mechanics of the hip and knee were visible at 50% of the participants’ maximal fatigue and became more marked at 100% fatigue. Anterior cruciate ligament injury-prevention programs should emphasize feedback on proper mechanics throughout an entire practice and not only at the beginning of practice.