Objectives: While the windmill pitch used in fast-pitch softball is considered by many to be safe compared to the overhead baseball pitch, there is little information that exists regarding the effects of the fatigue on fast-pitch softball pitchers. Recent biomechanical evidence suggests that the stress on the shoulder from the windmill pitch rivals that seen in baseball pitchers. We aim to characterize the effects of windmill pitching on pain, fatigue, range of motion (ROM) and strength in high school fast-pitch softball pitchers during a single season. Methods: We evaluated shoulder and elbow strength (dynamometer), ROM (goniometer), pain (visual analog scale (VAS)) and fatigue (VAS-fatigue and Borg questionnaire) in 21 (ages 15-18) high school fast-pitch softball pitchers before and after a single game during the first week of the high school softball season. Of the 21 pitchers, 17 were re-evaluated before and after a single game during the last week of the high school softball season with the aforementioned measurements. A study-team member recorded the number of pitches thrown by each pitcher for the games being evaluated. We recorded the number of games pitched by each pitcher during the high school season based on the pitchers’ report. Results: Of the 21 players, two players were injured mid-season and could not complete follow up. Two players were lost to follow-up. The average number of pitches thrown per player per game was 89±25 (range 30-161). The average games pitched was 12±5.7 (range 5-24). Supraspinatus (p<0.001), biceps (p<0.001), and external rotation strength in abduction and in neutral (p<0.001) decreased significantly post-game compared to pre-game regardless of the time of the season. Pain and fatigue were significantly higher post-game than pre-game (p<0.018) regardless of the time of the season. Pre-game VAS pain and fatigue at the end of the season correlated with the number games pitched during the season (r=0.66-0.73, p<0.006). There was an inverse linear relationship between games pitched and pre-game biceps, supraspinatus, and external rotation strength at the end of the season compared to beginning of season (r=-0.66-0.88, p<0.006). At the end of season compared to the beginning of season, there was a significant difference in pre-game pain, fatigue, biceps, supraspinatus, and external rotation strength between players who pitched more than 10 games versus players who pitched less than 10 games (p<0.033). Conclusion: Biceps and rotator cuff strength decrease significantly throughout the course of a game. Pitching more games during a season significantly increases pain and fatigue while significantly decreasing pre-game biceps and rotator cuff strength. Softball pitchers may be at increased risk of injury from fatigue during the course of a single game and over the entire season. Targeted strengthening as well as adequate rest intervals should be evaluated in these athletes.