Futility studies are designed to test new treatments over a short period in a small number of subjects to determine if those treatments are worthy of larger and longer term studies, or if they should be abandoned. An appropriate outcome measure for a neuroprotection futility study in Parkinson's disease (sensitive to tracking disease progression in the short-term) has not been determined. Data sets from three clinical trials were used to compare Parkinson's disease outcome measures. Total Unified Parkinson's Disease Rating Scale (UPDRS; Mentation + Activities of Daily Living + Motor) change and Motor plus Activities of Daily Living UPDRS change, measured in untreated patients, required the smallest sample sizes of all the outcome measures explored. Other outcomes (UPDRS Motor, UPDRS Activities of Daily Living, and time to need levodopa) required somewhat larger sample sizes. Futility designs in Parkinson's disease are feasible in terms of short duration and small sample size requirements, and this design is being applied in two ongoing Parkinson's disease studies to select agents for future larger and longer term neuroprotection studies. Ann Neurol 2005;57:197–203