Importance: This study aims to provide robust evidence to support or challenge the immune hypothesis of schizophrenia.

Objective: To conduct a meta-analysis of reports on blood leukocyte subpopulations in schizophrenia vs healthy controls, examining disease- and treatment-related differences as well as potential confounders.

Data sources: Systematic database search for English and non-English peer-reviewed articles in PubMed, Web of Science, Scopus, and Cochrane Library databases, with the last search in January 2024.

Study selection: Cross-sectional, case-control, and longitudinal studies comparing leukocyte numbers in patients with schizophrenia and healthy controls. After duplicates were removed, 3691 studies were identified for screening.

Data extraction and synthesis: Data extraction and quality assessment were conducted following PRISMA and MOOSE guidelines. Data were independently extracted by 2 authors and pooled using random-effects models.

Main outcomes and measures: The planned primary outcomes were differences in leukocyte subpopulation counts between individuals with schizophrenia and healthy controls to increase our understanding of the immune system dysfunction in schizophrenia.

Results: Sixty-four relevant articles were identified (60 cross-sectional/case-control studies and 4 longitudinal studies) with data on leukocyte numbers from 26 349 individuals with schizophrenia and 16 379 healthy controls. Neutrophils (g = 0.69; 95% CI, 0.49 to 0.89; Bonferroni-adjusted P < .001; n = 40 951 [47 between-group comparisons]) and monocytes (g = 0.49; 95% CI, 0.24 to 0.75; Bonferroni-adjusted P < .001; n = 40 513 [44 between-group comparisons]) were higher in schizophrenia compared with control participants. Differences were greater in first-episode vs chronic schizophrenia and in patients who were not treated vs treated with antipsychotic medication. There were no significant differences in eosinophils (g = 0.02; 95% CI, -0.16 to 0.20; Bonferroni-adjusted P > .99; n = 3277 [18 between-group comparisons]), basophils (g = 0.14; 95% CI, -0.06 to 0.34; Bonferroni-adjusted P = .85; n = 2614 [13 between-group comparisons]), or lymphocytes (g = -0.08; 95% CI, -0.21 to 0.06; Bonferroni-adjusted P > .99; n = 41 693 [59 between-group comparisons]). Neutrophils decreased longitudinally (g = -0.30; 95% CI, -0.45 to -0.15; Bonferroni-adjusted P < .001; n = 896 [4 within-group comparisons]) and eosinophils increased longitudinally (g = 0.61; 95% CI, 0.52 to 0.71; Bonferroni-adjusted P < .001; n = 876 [3 within-group comparisons]) after successful treatment of acute psychosis.

Conclusions and relevance: Our findings of increased blood neutrophils and monocytes support the immune hypothesis of schizophrenia, particularly highlighting the role of innate immune activation. As these effects were more pronounced in early disease stages and also reflected clinical improvement, they may pave the way for innovative treatment strategies based on immunological and inflammatory pathways and help revolutionize the treatment landscape for schizophrenia.