PURPOSE. To examine tear film, contact lens, medical, and patient-related factors associated with self-reported contact lens-related dry eye. METHODS. Four hundred fifteen contact lens wearers were recruited and enrolled in this phase of a larger cross-sectional study. A variety of tear film (e.g., interferometry, osmolality, phenol red thread, meibography, fluorescein, and lissamine green staining), contact lens (i.e., water content, refractive index, material), and patient-related (e.g., gender, sociodemographic, education, income, and medical health) factors were examined in relation to dry eye status. Univariate and multivariate logistic regression models were used to examine the relation between these tear film, contact lens, and patient-related factors associated with dry eye status. RESULTS. Of the 415 enrolled, the data from 360 were used in the analyses. The average age was 31.1 ± 11.5 years, 245 (68%) participants were female, and 55.3% were classified as having-contact lens-related dry eye via self-report. Overall, 327 (90.8%) were hydrogel lens wearers and 33 (9.2%) were gaspermeable lens wearers. Several factors were shown to be related to dry eye status in multivariate modeling, including female gender (P = 0.007), lenses with higher nominal water content (P = 0.002), rapid prelens tear film thinning time (P = 0.008), frequent usage of over-the-counter pain medication (P = 0.02), limbal injection (P = 0.03), and increased tear film osmolality (P = 0.05). CONCLUSIONS. Contact lens-related dry eye may be explained mechanistically by increased tear film thinning times (evaporation or dewetting) resulting in increased tear film osmolality. Other contributing factors include the use of high-water-content lenses, which have traditionally been reported to be associated with less patient comfort than lower-water-content lenses, potentially due to spoilation and deposition. As found in other studies of dry eye, women are more likely to report contact lens-related dry eye than are men. Copyright © Association for Research in Vision and Ophthalmology.