Background: The effects of approaching muscular fatigue on pitching biomechanics are currently unknown. As a pitcher fatigues, pitching mechanics may change, leading to a decrease in performance and an increased risk of injury. Hypothesis: As a pitcher approaches muscular fatigue, select pitching biomechanical variables will be significantly different than they were before muscular fatigue. Study Design: Controlled laboratory study. Methods: Ten collegiate baseball pitchers threw 15 pitches per inning for 7 to 9 innings off an indoor throwing mound during a simulated baseball game. A pitching session ended when each pitcher felt he could no longer continue owing to a subjective perception of muscular fatigue. A 6-camera 3D automatic digitizing system collected 200-Hz video data. Twenty kinematic and 11 kinetic variables were calculated throughout 4 phases of the pitch. A repeated-measure analysis of variance (P <.01) was used to compare biomechanical variables between innings. Results: Compared with the initial 2 innings, as a pitcher approached muscular fatigue during the final 2 innings he was able to pitch, there was a significant decrease in ball velocity, and the trunk was significantly closer to a vertical position. There were no other significant differences in kinematics or kinetics variables. Conclusion: The relatively few differences observed imply that pitching biomechanics remained remarkably similar between collegiate starting pitchers who threw between 105 and 135 pitches for 7 to 9 innings and approached muscular fatigue. Clinical Relevance: This study did not support the idea that there is an increase in shoulder and elbow forces and torques as muscular fatigue is approached. It is possible that if a pitcher remained in a fatigued state for a longer period of time, additional changes in pitching mechanics may occur and the risk of injury may increase. © 2007 American Orthopaedic Society for Sports Medicine.