Resistance training is commonly used in sports for prevention of injuries and in rehabilitation. The purpose of this study was to compare closed vs. open kinetic chain weight training of the thigh muscles and to determine which mode resulted in the greatest performance enhancement. Twenty-four healthy subjects were randomized into a barbell squat or a knee extension and hip adduction variable resistance weight machine group and performed maximal, progressive weight training twice a week for 6 weeks. All subjects were tested prior to training and at the completion of the training period. A barbell squat 3-repetition maximum, an isokinetic knee extension 1-repetition maximum, and a vertical jump test were used to monitor effects of training. Significant improvements were seen in both groups in the barbell squat 3-repetition maximum test. The closed kinetic chain group improved 23 kg (31%), which was significantly more than the 12 kg (13%) seen in the open kinetic chain group. In the vertical jump test, the closed kinetic chain group improved significantly, 5 cm (10%), while no significant changes were seen in the open kinetic chain group. A large increase of training load was observed in both subject groups; however, improvements in isotonic strength did not transfer to the isokinetic knee extension test. The results may be explained by neural adaptation, weight training mode, and specificity of tests.