Loading using variable resistance devices, where the external resistance changes in line with the force:angle relationship, has been shown to cause greater acute neuromuscular fatigue and larger serum hormone responses. This may indicate a greater potential for adaptation during long-term training. Twelve (constant resistance group) and 11 (variable resistance group) men completed 20 weeks of resistance training with 10 men as non-training controls. Training-induced adaptations were assessed by bilateral leg press one repetition maximum, a repetition to failure test using 75 % 1RM, lower limb lean mass and vastus lateralis cross-sectional area. Only the variable resistance training group improved the total number of repetitions (41 ± 46 %) and volume load (52 ± 37 %) during the repetition to failure test (P < 0.05). Similar improvements in maximum strength and hypertrophy of the lower limbs were observed in both training groups. Also, constant and variable resistance 5 × 10RM leg press loadings were performed before and after training in a crossover design. Acute loading-induced responses were assessed by concentric and isometric force, serum hormone concentrations and phosphorylation of intramuscular signalling proteins (0-30 min post-loading). Greater acute decreases in force (P < 0.05-0.01), and greater increases in serum testosterone and cortisol concentration (P < 0.05) and ERK 1/2 phosphorylation (P < 0.05) were observed following variable resistance loadings before and after training. Greater training-induced improvements in fatigue resistance occurred in the variable resistance training group, which may be due to greater acute fatigue and physiological responses during variable versus constant resistance loadings.