Herpes simplex encephalitis (HSE) patients may develop secondary anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis (NMDARE), associated with worsened long-term neurological outcome. Immunosuppressive treatment can limit NMDAR autoantibody-mediated pathology, but early predictive biomarkers for the risk of NMDARE are lacking. In a multicenter study, we performed unbiased antibody reactome profiling using Phage ImmunoPrecipitation Sequencing (PhIP-Seq). HSE patients with secondary NMDARE (n = 13) versus those without (n = 10) showed enhanced antibody responses against HSV-1, but not HSV-2, which comprised specific antibodies to five peptides of the HSV-1 UL42 and UL48 proteins. A score of these signature CSF antibodies identified HSE patients with secondary NMDARE with a sensitivity of 75%, a specificity of > 99%, a positive predictive value of 90%, a negative predictive value of > 97% and an odds ratio (OR) of 209 (CI: 28 - 1,582) across all individuals in this study, and with similar performance values in serum (>66%, >99%, >88%, >96%, OR 307 (15 - 6,089)). These signature antibodies represent a promising biomarker to identify HSE patients at risk for NMDARE development. In NMDARE patients without a history of HSE and in MS patients, no disease-associated HSV antibody reactivity patterns were detected. Furthermore, we introduced the Multiplexed Index Calculations of the Antibody Reactome (MICAR) metric to characterize proteomic targets of compartment-specific antibody responses, an approach that is applicable in neuroimmunology and other compartmentalized disease states.