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Purpose: To evaluate the effect of femtosecond laser-assisted cataract surgery (FLACS) and manual cataract surgery (MCS) on proinflammatory cytokine expression in patients with diabetes vs nondiabetic patients., Setting: Outpatient surgical center in Vaughan, Ontario, Canada., Design: Prospective cohort study., Methods: Patients with diabetes and nondiabetic patients undergoing noncomplicated MCS or FLACS were assigned into 4 cohorts: MCS nondiabetic (n = 30), FLACS nondiabetic (n = 42), MCS diabetic (n = 40), and FLACS diabetic (n = 40). Aqueous humor inflammatory mediator concentrations were evaluated at MCS onset and after femtosecond laser treatment. The presence of cystoid macular edema, anterior chamber (AC) inflammation, central retinal thickness, macular volume, and retinal microvascular changes (through optical coherence tomography angiography) were evaluated preoperatively and on postoperative day 1, week 1, month 1 (POM1), and month 3 (POM3)., Results: Patients with diabetes receiving FLACS had a higher concentration of interleukin (IL)-7, IL-13, and interferon-induced protein-10 than MCS diabetic patients; they also demonstrated higher levels of vascular endothelial growth factor and lower levels of interferon (IFN)-γ, granulocyte colony-stimulating factor, and IFN-α2 compared with MCS nondiabetic patients. Macular volume appeared to be significantly higher in MCS diabetic vs MCS non-diabetic patients at POM1 and between FLACS diabetic vs FLACS nondiabetic patients at POM3. There were no other significant differences between the cohorts for any parameter., Conclusions: FLACS use in patients with diabetes demonstrated some differences in AC cytokine expression compared with non-diabetic FLACS or diabetic patients undergoing MCS; however, there was no increase in clinical inflammatory biomarkers. FLACS seems to be a safe technique to use in patients with diabetes., (Copyright © 2023 Published by Wolters Kluwer on behalf of ASCRS and ESCRS.)