<p>Brain macromolecule signals detected with proton magnetic resonance spectroscopy (MRS) are often regarded as a nuisance, but may be potential markers of pathophysiological processes, such as inflammation, impaired glymphatic clearance, and damage to cellular membranes. To date, there is little published data on macromolecule levels in schizophrenia spectrum disorders (SSD). In this study, we used metabolite-nulled proton MRS to assess macromolecule signals in four brain regions of interest, the anterior cingulate cortex, striatum, hippocampus, and white matter, in 24 people with SSD and 22 healthy controls. Participants were also assessed for cognitive performance and blood levels of C-reactive protein (CRP), an inflammatory marker. There were significant differences in macromolecule levels between people with SSD and controls in the left hippocampus. There were no significant associations of macromolecule levels with cognition, symptom severity, or CRP levels. There were significant associations of macromolecule levels in the striatum with current antipsychotic dose in the SSD group, and macromolecule levels in the anterior cingulate with subjective sleep quality. Except for the slight reductions in hippocampus, these results suggest that macromolecules may not be notably different in SSD and may not significantly impact MRS metabolite measures collected with short TE sequences, although larger studies are needed to confirm.</p>