Objectives: To investigate ocular surface alterations and in vivo confocal microscopic characteristics of the cornea in dry eye disease (DED) with contact lens wear (CLW). Methods: Sixty participants were divided into three groups: DED with CLW (n=20), DED without CLW (n=20), and normal control (n=20). Ocular surface parameters were evaluated. Basal tears and in vivo confocal microscopy images of the cornea were collected. Multiplex bead analysis was used to assess interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α, nerve growth factor (NGF), and substance P (SP) in tears. Nerve morphology and dendritic cell density in corneal subbasal nerve images were calculated. Results: The DED with CLW group showed significantly higher ocular surface staining scores (P=0.022) and higher levels of IL-1β, NGF, and SP in tears (P=0.014, P=0.004 and P=0.025) than the DED without CLW group. Corneal dendritic cell density in the DED with CLW group was significantly higher than that in the normal controls (P=0.001) and DED without CLW group (P=0.043). Tear cytokine levels of IL-1β, NGF, and SP were correlated with ocular surface parameters in the DED with CLW group. Moreover, the years of CLW were positively correlated with corneal dendritic cell density (r=0.527, P=0.017) and negatively correlated with corneal nerve density (r=−0.511, P=0.021). Conclusions: Patients with DED with CLW showed greater epithelial damage, elevated inflammatory cytokines and neuromediators in tears, and higher corneal dendritic cell density than patients with DED without CLW. The immune and nervous systems may be involved in contact lens–related DED.