Calcium-binding protein B (S100B), a primary product of astrocytes, is a proposed marker of Parkinsońs disease (PD) pathophysiology, diagnosis and progression. However, it has also been implicated in sleep disruption, which is very common in PD. To explore the relationship between S100B, disease severity, sleep symptoms and polysomnography (PSG) findings, overnight changes in serum S100B levels were investigated for the first time in PD. 17 fully treated, non-demented, moderately advanced PD patients underwent PSG and clinical assessment of sleep symptoms. Serum S100B samples were collected immediately before and after the PSG. Results are shown as median [interquartile range]. Night and morning S100B levels were similar, but uncorrelated (rs = -0.277, p=0.28). Morning S100B levels, as opposed to night levels, positively correlated with the Unified Parkinson's disease rating scale (UPDRS) subsections I and II (rs = 0.547, p=0.023; rs = 0.542, p=0.025). Compared to those with overnight S100B reduction, patients with overnight S100B elevation had higher H&Y scores (2.5 [0.87] vs. 2 [0.25], p=0.035) and worse total Pittsburgh Sleep Quality Index (PSQI) and Parkinsońs Disease Sleep Scores (10 [3.2] vs. 8 [4.5], p=0.037; 92.9 [39] vs. 131.4 [28], p=0.034). Correlation between morning S100B levels and total UPDRS score was strengthened after controlling for total PSQI score (rs = 0.531, p=0.034; partial rs = 0.699, p=0.004, respectively). Overnight S100B variation and morning S100B were associated with PD severity and perceived sleep disruption. S100B is proposed as a putative biomarker for sleep-related neuroinflammation in PD. Noradrenergic-astrocytic dysfunction is hypothesized as a possible mechanism underlying these findings.