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Purpose: Boston keratoprosthesis (KPro) patients are prone to glaucoma even with well-controlled intraocular pressure (IOP). Recent experimental data have shown that soluble tumor necrosis factor alpha (TNF-α) after ocular injury may contribute to progressive retinal damage and subsequent glaucoma. This study evaluates the blood plasma levels of soluble TNF-α, TNF receptors 1 (TNFR1) and 2 (TNFR2), and leptin in patients with Boston type I KPro. Methods: Venous blood samples were collected from KPro patients with glaucoma (KPro G, n = 19), KPro patients without glaucoma (KPro NoG, n = 12), primary angle closure glaucoma without KPro (PACG, n = 13), and narrow angles without glaucoma or KPro (NA, n = 21). TNF-α, TNFR1, TNFR2, and leptin levels were quantified using the enzyme-linked immunosorbent assay. Erythrocyte sedimentation rate (ESR) was assessed using the Westergren test. Patients with underlying autoimmune conditions or diabetes were excluded from the study. Results: All groups had similar age, body mass index (BMI), IOP, and ESR (p ≥ 0.11). The mean time from KPro surgery to blood draw was 5.3 ± 3.7 years. Compared to NA patients (0.72 ± 0.3 pg/ml), KPro G and KPro NoG patients had higher blood plasma levels of TNF-α (1.18 ± 0.58 pg/ml, p = 0.006; 1.16 ± 0.50 pg/ml, p = 0.04, respectively). Similarly, KPro G patients had higher blood plasma levels of TNFR2 (2768 ± 1368 pg/ml) than NA patients (2020 ± 435 pg/ml, p = 0.048). In multivariate analysis, KPro status remained positively associated with TNF-α levels (β = 0.36; 95% confidence intervals [CI]: 0.14–0.58; p = 0.002) and TNFR2 levels (β = 458.3; 95% CI: 32.8–883.7; p = 0.035) after adjusting for age, gender, BMI, glaucoma status, and ESR. TNFR1 and leptin levels were not significantly different in the study groups. Conclusions: We detected elevated serum levels of TNF-α and TNFR2 in KPro patients. Longitudinal studies are needed to establish TNF-α and TNFR2 as serum biomarkers related to KPro surgery. Abbreviations: BCVA: best corrected visual acuity; BMI: body mass index; CDR: cup-to-disc ratio; EDTA: ethylenediaminetetraacetic acid; ELISA: enzyme-linked immunosorbent assay; ESR: erythrocyte sedimentation rate; HVF: Humphrey visual field; IOP: intraocular pressure; KPro G: keratoprosthesis with glaucoma; KPro NoG: keratoprosthesis without glaucoma; KPro: keratoprosthesis; MD: mean deviation; NA: narrow angle; non-KPro: without keratoprosthesis; PACG: primary angle closure glaucoma; RNFL: retinal nerve fiber layer; TNF-α: tumor necrosis factor alpha; TNFR1: tumor necrosis factor receptor 1; TNFR2: tumor necrosis factor receptor 2 [ABSTRACT FROM AUTHOR]