SIGNIFICANCE Early diagnosis of clinical markers of contact lens discomfort can help clinicians set realistic expectations and monitor and provide prophylactic management for contact lens wearers. PURPOSE The purpose of this study was to evaluate the potential of eyelid- and tear film-related clinical markers to be used as predictive factors for diagnosing discomfort in contact lens wearers. METHODS A cross-sectional study was performed on 30 contact lens wearers (6 male, 24 female) with median age of 23 years (range, 18 to 41 years). Eyelid signs and tear film characteristics were evaluated during a single visit, and subjects completed the Contact Lens Dry Eye Questionnaire to evaluate ocular discomfort. Area under the curve (AUC) statistics and sensitivity and specificity values from receiver operating characteristic curves were analyzed to evaluate the predictive potential of clinical signs in discriminating symptoms of contact lens discomfort. RESULTS The presence of foam at meibomian gland orifices (AUC, 0.944; P <.05; sensitivity >0.7), meibomian gland secretion volume (AUC, 0.935; P <.05; sensitivity >0.7), quality (AUC, 0.969; P <.05; sensitivity >0.7), and expressibility (AUC, 0.933; P <.05; sensitivity >0.7) were significant and strong predictors of discomfort in lens wear. Tear evaporation rates with (AUC, 0.779; P <.05; sensitivity >0.7) or without contact lenses (AUC, 0.788; P <.05; sensitivity >0.7), palpebral conjunctival roughness (AUC, 0.859; P <.05; sensitivity >0.7), palpebral conjunctival staining (AUC, 0.817; P <.05; sensitivity >0.7), palpebral conjunctival hyperemia (AUC, 0.746; P <.05; sensitivity >0.7), meibomian gland orifice capping (AUC, 0.873; P <.05; sensitivity >0.7), pouting (AUC, 0.891; P <.05; sensitivity >0.7), and lid-parallel conjunctival folds (AUC, 0.770; P <.05; sensitivity >0.7) were other acceptable discriminators of symptoms of discomfort during contact lens wear. An equation was developed to identify symptomatic from asymptomatic lens wearers based on the significant predictors: Symptom discriminant function score = 3.378 (meibomian gland secretion grade) + 0.224 (meibomian gland morphology grade) + 0.61 (tear evaporation rate without contact lenses) + 0.439 (lid-parallel conjunctival folds grade) - 0.346 (palpebral conjunctival health grade) - 4.625. CONCLUSIONS This study demonstrated that clinical signs related to meibomian gland secretions and morphology, tear evaporation, lid-parallel conjunctival folds, and palpebral conjunctival health may successfully predict symptoms of discomfort in contact lens wearers.