No study has examined the effect of exercise modality (free weight vs. machine weight) on the acute hormonal response using similar multi-joint exercises. The purpose of this investigation was to examine the effect of resistance exercise modality on acute hormonal responses by comparing the squat and leg press which are multi-joint, and similar in action and lower-body muscle involvement. Ten resistance trained men (21-31 y, 24.7 ± 2.9 y, 179 ± 7 cm, 84.2 ± 10.5 kg) participated in the study. Sessions 1 and 2 determined the participants’ 1-RM in the squat and leg press. During acute heavy resistance exercise testing visits (AHRET), sessions 3 and 4, participants completed 6 sets of 10 repetitions with an initial intensity of 80% of their 1-RM for the squat and leg press exercises. There was a 2 minute rest period between each set. Blood samples were collected before, immediately after, and 15 and 30 minutes after exercise via intravenous catheter during the AHRET visits and were analyzed for testosterone, cortisol, and growth hormone. Lactate, plasma volume change, heart rates and ratings of perceived exertion were also measured. Total work was calculated for external load only and for external load and the body mass used in the exercises. The 4 sessions were counterbalanced and randomized for exercise mode. Testosterone for the squat (Pre: 23.9 ± 8.7 nmol•L-1; IP: 31.4 ± 10.3 nmol•L) and leg press (Pre: 22.1 ± 9.4 nmol•L-1; IP: 26.9 ± 7.8 nmol•L) increased but more significantly after the squat. Growth hormone increased in both the squat (Pre: 0.2 ± 0.2 µg/L; IP: 9.5 ± 7.3 µg/L) and the leg press (Pre: 0.3 ± 0.5 µg/L; IP: 2.8 ± 3.2 µg/L). The increase was significantly higher after the squat compared to the leg press. Cortisol also increased after performing the squat (Pre: 471.9 ± 167.2 nmol•L-1; IP: 603.2 ± 277.6 nmol•L) and leg press (Pre: 463.5 ± 212.4 nmol•L-1; IP: 520.3 ± 270.3 nmol•L), but there was no significant difference between the two modes. The total work was significantly higher in the squat (60509 ± 10759 j) compared to the leg press (42875 ± 7010). The squat exercise is more effective at inducing an acute hormonal response. If the leg press exercise is used, the hormonal response may be reduced, which might lead to reduced training adaptations, especially when only a 90º knee angle ROM is used. To induce the maximal hormonal response to resistance exercise, free weight exercises should be used.