Throwing is a vigorous activity that generates large internal loads. There is limited evidence of the effect of these loads on bone adaptation. The aim of this study was to investigate the 1) magnitude of bone adaptation within the midshaft humerus of female fast-pitch softball players and 2) influence of throwing mechanics (windmill vs overhand throwing) on the magnitude of adaptation.Midshaft humeral bone mass, structure, and estimated strength were assessed via peripheral quantitative computed tomography in fast-pitch softball players (throwers; n = 15) and matched controls (controls; n = 15). The effect of throwing was examined by comparing dominant-to-nondominant differences in throwers to controls, whereas the influence of mechanics was determined by comparing dominant-to-nondominant differences in throwers who primarily play as pitcher (windmill thrower), catcher (overhand thrower), or fielder (overhand thrower).Throwers had greater dominant-to-nondominant difference in midshaft humeral bone mass, structure, and estimated strength relative to controls (all P < 0.05). The largest effect was for estimated torsional strength with throwers having a mean dominant-to-nondominant difference of 22.5% (range = 6.7%-43.9%) compared with 4.4% (range = -8.3% to 17.5%) in controls (P < 0.001). Throwing mechanics seemed to influence the magnitude of skeletal adaptation, with overhand throwers having more than double dominant-to-nondominant difference in midshaft humeral bone mass, structure, and estimated strength than windmill throwers (all P < 0.05).Throwing induces substantial skeletal adaptation at the midshaft humerus of the dominant upper extremity. Throwing mechanics seems to influence the magnitude of adaptation, as catchers and fielders (overhand throwers) had twice as much adaptation as pitchers (windmill throwers). The latter finding may have implications for skeletal injury risk at the midshaft humerus in throwing athletes.