Atypical antipsychotics (AA) are generally associated with weight gain. We determined body mass index (BMI) change in Parkinson's disease (PD) before and after taking AA and compared against PD controls and Alzheimer's disease (AD) patients on AA. In 66 consecutive PD subjects started on AA who had accurate weights for more than 6 months before and after initiation of AA, we compared weight change before and after AA use, against a control group of sixty-one sex-matched PD subjects, and against twenty-eight AD subjects taking AA. A linear regression model was created to compare weight changes. Fifty-nine PD subjects had complete data, quetiapine (n=53) and clozapine (n=6). The mean BMI change in the period before starting AA was 0.00 kg/m(2)/month over 1.95+/-1.41 years. After starting AA, subjects lost 0.03 kg/m(2)/month (95% CI 0.62-1.21, P<0.0001), comparing PD before AA to the same PD patients after AA. In 61 PD controls, the mean BMI loss was 0.01 kg/m(2)/month (95% CI 0.15-0.94, P=0.007) comparing PD on AA vs. PD controls. The BMI for 28 AD subjects on AA increased 0.01 kg/m(2)/month (95% CI 0.26-0.83, P<0.0001), comparing PD on AA vs. AD on AA. The weight loss seen in the PD/AA group, compared to AD, suggest uniquely altered weight homeostasis in PD.