Purpose: This study compared the effects of resistance training (RT) and RT with instability (RTI) on neuromuscular and total training volume (TTV) outcomes obtained as part of the Instability Resistance Training Trial in Parkinson's disease. It also used a linear multiple regression (forward stepwise method) to identify the contribution of neuromuscular outcomes to previously published improvements in the timed-up-and-go test and the Unified Parkinson's Disease Rating Scale, motor subscale score. Methods: Thirty-nine patients with moderate to severe Parkinson's disease were randomly assigned to three groups: control (C), RT, and RTI. RT and RTI groups performed resistance exercises twice a week for 12 wk, and only the RTI group used unstable devices to perform resistance exercises. The following neuromuscular outcomes were assessed: quadriceps muscle cross-sectional area, root mean square and mean spike frequency of electromyographic signal, peak torque, rate of torque development, and half relaxation time of the knee extensors and plantarflexors during maximum ballistic voluntary isometric contractions. TTV was calculated for lower limb exercises. Results: From pre-to posttraining, RTI improved all of the neuromuscular outcomes (P < 0.05) except half relaxation time of the knee extensors (P = 0.068), despite the lower TTV than RT (P < 0.05). RTI was more effective than RT in increasing the root mean square values of vastus medialis, mean spike frequency of gastrocnemius medialis, and rate of torque development of plantarflexors (P < 0.05). Stepwise regression identified the changes in mean spike frequency of gastrocnemius medialis as the best predictor of improvements in timed-up-and-go test (R-2 = 0.58, P = 0.002) and on-medication Unified Parkinson's Disease Rating Scale, motor subscale scores (R-2 = 0.40, P = 0.020). Conclusion: RTI optimizes neuromuscular adaptations, which partially explains mobility and motor sign improvements in patients with Parkinson's disease.