In order to evaluate the therapeutic value of an unpreserved carboxymethylcellulose-based artificial tear in treatment of keratoconjunctivitis sicca (KCS), 56 patients with severe keratoconjunctivitis sicca were enrolled, at a single study center, in a randomized, double-masked, 8-week comparison with a preserved hydroxypropylmethylcellulose (HMC)-based artificial tear. Patients treated with the carboxymethylcellulose (CMC)-based tear showed significant improvement in fluorescein staining, symptoms, and impression cytology grades. Patients treated with HMC-based tears showed minimal improvement in a few variables. Impression cytology specimens were analyzed by a modified technique that maps the distribution of the various grades present on the specimen. With this technique, improvement in the cytology grades was noted in the group of patients using CMC-based tears. The improvement correlated with observed decreases in symptoms of discomfort and with scores for superficial punctate staining. This study supports the observed therapeutic value of unpreserved CMC-based artificial tears and suggests the possible reversal of squamous metaplasia in patients with KCS. Further studies are required to separate the benefit of the CMC formulation from the benefits of preservative elimination.