Objective To investigate the relationship of novelty seeking traits (NS) with midbrain dopamine (DA) receptors and acyl ghrelin levels (AG) in normal weight (NW) and obese females.NS predict addictive behaviors and are hypothesized to contribute to eating behaviors. In healthy, NS are negatively associated with DA receptors in the substantia nigra (SN). The influence of obesity on the regulation of NS by DA signaling and AG was hypothesized. Methods PET scanning to measure DA type 2/type 3 receptor (D2/D3R) binding potential (BPND) in the SN was used. Participants completed Tridimensional Personality Questionnaire-Novelty-Seeking Scale (TPQ-NS) and AG were measured. Results In eight NW and 19 obese (BMI 22 vs 38 kg/m2), TPQ-NS (16 vs 15) and SN D2/D3R BPND (2.48 vs 2.66) were similar, while AG higher (256 vs 60, P<0.01), respectively. D2/D3R BPND and TPQ-NS had a negative relationship in NW (r=-0.7) but not in obese (P>0.10). AG and TPQ-NS were positively correlated in NW (r=0.9) but not in obese (P>0.10). D2R BPND and AG were negatively correlated in NW (r=-0.8) but positively in obese (r=0.6). Conclusion Obese do not maintain posited regulatory relationships for NS to either midbrain D2/D3R availability or AG present in NW. Also opposite relationships exist for NW and obese between SN D2/D3R availability and AG. The altered regulation of NS in obesity needs to be further explored.