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• We explored a range of predictor machines and feature subset selector machines. • LOLIMOT was seen as the best predictor machine. • GA and ACO were the best feature subset selector machines. • Five important features were identified for optimal prediction of motor outcome in PD. • Motor (MDS_UPDRS-III) prediction error of 4.15 ± 0.46 was reached, outperforming prior efforts. It is vital to appropriately power clinical trials towards discovery of novel disease-modifying therapies for Parkinson's disease (PD). Thus, it is critical to improve prediction of outcome in PD patients. We systematically probed a range of robust predictor algorithms, aiming to find best combinations of features for significantly improved prediction of motor outcome (MDS-UPDRS-III) in PD. We analyzed 204 PD patients with 18 features (clinical measures; dopamine-transporter (DAT) SPECT imaging measures), performing different randomized arrangements and utilizing data from 64%/6%/30% of patients in each arrangement for training/training validation/final testing. We pursued 3 approaches: i) 10 predictor algorithms (accompanied with automated machine learning hyperparameter tuning) were first applied on 32 experimentally created combinations of 18 features, ii) we utilized Feature Subset Selector Algorithms (FSSAs) for more systematic initial feature selection, and iii) considered all possible combinations between 18 features (262,143 states) to assess contributions of individual features. A specific set (set 18) applied to the LOLIMOT (Local Linear Model Trees) predictor machine resulted in the lowest absolute error 4.32 ± 0.19, when we firstly experimentally created 32 combinations of 18 features. Subsequently, 2 FSSAs (Genetic Algorithm (GA) and Ant Colony Optimization (ACO)) selecting 5 features, combined with LOLIMOT, reached an error of 4.15 ± 0.46. Our final analysis indicated that longitudinal motor measures (MDS-UPDRS-III years 0 and 1) were highly significant predictors of motor outcome. We demonstrate excellent prediction of motor outcome in PD patients by employing automated hyperparameter tuning and optimal utilization of FSSAs and predictor algorithms. [ABSTRACT FROM AUTHOR]