Purpose <p>We compared locus coeruleus (LC) structural integrity, as measured by neuromelanin-sensitive magnetic resonance imaging (NM-MRI), between patients with Parkinson’s disease (PD) and those with multiple system atrophy (MSA) and tested whether orthostatic hypotension (OH) impacted differences in LC volume between PD and MSA. Substantia nigra (SNc) volumes were compared between these groups to determine whether effects observed in LC were specific to that structure. Last, we tested whether LC integrity is associated with orthostatic hemodynamic responses.</p> Methods <p>Presence or absence of (±)OH was determined with active stand testing. Automated segmentation of LC and SNc volumes took place using NM-MRI. Structural volumes were first compared between PD and MSA groups and, second, after stratification by OH status. Last, correlations between LC volumes and orthostatic vitals were calculated.</p> Results <p>Of 71 patients with PD, 19 were (+)OH. Of 19 patients with MSA, 12 were (+)OH. LC volumes were larger in PD than MSA (<i>p</i> = 0.002), and LC volumes in PD(−)OH were larger than PD(+)OH and MSA(±)OH (<i>p</i> &lt; 0.05). All comparisons involving SNc were nonsignificant. Primarily in PD(−)OH, LC volumes correlated negatively with supine mean arterial pressure (MAP) and positively with supine heart rate. In PD(+OH) and MSA(+)OH, lower LC volumes were correlated with greater orthostatic falls in MAP.</p> Conclusions <p>Similar levels of LC neurodegeneration were observed in PD(+)OH and MSA(±)OH. Therefore, LC measurement may be useful to differentiate PD(−)OH from MSA.&#xa0;Lower LC volumes additionally correlated with greater drops in MAP in both PD(+)OH and MSA(+)OH, suggesting that&#xa0;LC neurodegeneration may contribute to OH in both conditions.</p>