BackgroundAccurate antemortem EPM diagnosis requires evidence of intrathecal antibody production. Some advocate the use of acute phase proteins in addition to serology, which alone results in substantial false positives.Hypothesis/ObjectivesThe purpose of this study was to determine if serum C‐reactive protein (CRP) or serum amyloid A (SAA) concentrations were elevated in cases of equine protozoal myeloencephalitis (EPM) compared to other neurological diseases.Animals25 clinical cases of equine neurological disease: EPM (10), cervical vertebral stenotic myelopathy (CVSM) (10), neuroborreliosis (2), equine motor neuron disease (1), degenerative myelopathy (1), and leukoencephalomalacia (1).MethodsSerum and CSF CRP and SAA were measured. Selection criteria included neurologic disease, antemortem diagnosis of EPM or CVSM, or postmortem diagnosis of EPM, CVSM, or other neurologic disease, and availability of serological results and archived samples for testing.ResultsSerum SAA and serum CRP levels were generally undetectable or low in horses with EPM (median CRP ≤0.1 mg/L, ≤0.1‐14.4 mg/L; median SAA ≤0.1 mg/L, ≤0.1‐6.11 mg/L) and CVSM (median CRP ≤0.1, ≤0.1‐2.41 mg/L; median SAA ≤0.1mg/L, ≤0.1‐13.88 mg/L). CSF CRP and SAA for horses with EPM (median CRP 3.35 mg/l, 0.19‐13.43 mg/l; median SAA ≤0.1 mg/L, ≤0.1‐2.4 mg/L) and CVSM (median CRP 4.015 mg/L, 0.16‐9.62 mg/L; median SAA 0.62 mg/L, ≤0.1‐2.91 mg/L) were also undetectable or low. Kruskal–Wallis test showed no statistically significant differences between serum CRP (P = .14), serum SAA (P = .79), spinal fluid CRP (P = .65), or spinal fluid SAA between horses with EPM and CVSM (P = .52).ConclusionNeither SAA nor CRP in serum or CSF aid diagnosis of EPM.