To investigate the differential expression of tear cytokine levels among chronic Stevens-Johnson syndrome (SJS) patients to better understand the role of significantly altered cytokines in disease development. Tear samples were collected using Schirmer strips in 24 eyes of chronic SJS, 24 eyes of age and gender-matched controls, and 14 eyes of aqueous deficiency dry eye disease (DED) patients. The cytokine analysis was performed among 18 analytes which include pro-inflammatory, anti-inflammatory factors, and ELR-negative CXC chemokines. String analysis was performed for the significantly altered cytokines to understand their co-expression and role in the disease development. Additionally, a literature review was conducted to identify the signature cytokines present in chronic SJS tears. The differential expression of IL-6 (p ≤ 0.029), CXCL8/IL-8 (p ≤ 0.009), IL-1β (p ≤ 0.041), IL-2 (p ≤ 0.025), IL-10 (p ≤ 0.053), and CXCL-10 (p ≤ 0.044) were observed in chronic SJS patients and healthy controls. Whereas, IL-6 (p ≤ 0.029), CXCL8/IL-8 (p ≤ 0.058), CCL4 (p ≤ 0.056), GM-CSF (p ≤ 0.0001) IL-10 (p ≤ 0.025), and CXCL-10 (p ≤ 0.010), were differentially expressed in SJS as compared to severe DED patients. String analysis of the significantly altered cytokines revealed the involvement of several biological processes including the chronic inflammatory response, nitric oxide synthesis, angiogenesis, and cellular response to drugs. Among all the cytokines evaluated, the expression of CXCL8/IL-8 and CXCL10 levels were consistently reported in the literature. There was a differential expression of tear cytokines in SJS when compared to DED and healthy controls. The differential expression of CXCL8/IL-8 and CXCL10 was in line with existing literature and their role in chronic SJS pathogenesis merits further evaluation.