<p>More than 20% of individuals with schizophrenia show minimal or no response to antipsychotic medications and little is known about genetic contributions to more severe forms of illness. This study sought to explore if cases with continuously-hospitalized, treatment-resistant schizophrenia (CH-TRS) carry a higher burden of common genetic variants compared to less severe forms. CH-TRS cases were recruited from Pennsylvania state psychiatric hospitals in the USA, with ≥ 5 years of continuous hospitalization, active treatment, and non-response to ≥ 3 antipsychotic medications. Three comparator groups were obtained from cohorts in the USA, Sweden, and the UK including TRS, general schizophrenia and non-psychiatric controls. Polygenic scores (PGS) of schizophrenia and cognitive ability were generated in individuals of European and African ancestry. Logistic regression assessed the association of PGS and CH-TRS cases (vs. comparators), with sex differences and sensitivity analyses excluding individuals with other diagnoses conducted to assess robustness. We included 18,571 individuals of European ancestry (346 CH-TRS, 10,757 TRS, 1148 general schizophrenia, 6320 non-psychiatric controls) and exploratory analyses of 476 individuals of African ancestry (78 CH-TRS, 398 non-psychiatric controls). For each standard deviation increase in the schizophrenia PGS, the odds of CH-TRS among individuals of European ancestry increased by 40–80% compared to general schizophrenia and TRS. Results in African ancestry participants mirrored those of European ancestry albeit with reduced levels of significance. Sex interactions and sensitivity analyses did not materially alter the estimates. This study demonstrates a greater burden of common genetic variants is associated with more severe forms of illness in schizophrenia.</p>