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PURPOSE: The aim of this work was to evaluate ultrastructural alterations of the conjunctiva during the clinical course of keratoconjunctivitis sicca (KCS), and to detect its earliest and most characteristic morphological changes. METHODS: The conjunctiva was studied in biopsies from 75 patients and 10 controls. Patients were classified according to the results of the Schirmer I test, break-up time, rose Bengal staining, osmolarity and impression cytology. RESULTS: The conjunctiva in these KCS patients showed progressive hyperplasia, hypertrophy and cellular flattening, with diminution of goblet cell density and microvilli. In the severe cases, the epithelial cells lost their organelles, and fibrous material increased. From the early phases of KCS, clear nuclear alterations (indentation, binucleation) were found, but pyknotic nuclei or anucleated cells were only observed in the most severe cases. From the earliest stages to the most severe cases of KCS, decreases in cell membrane interdigitations were observed parallel to increases in the number and size of desmosomes. There were also increases in the number of inflammatory cells. Alterations in blood vessels were only observed in the most severe cases. CONCLUSIONS: Morphological studies alone were able even in the earliest phases of KCS, to detect the squamous metaplasia that progresses from the surface of the epithelium to the connective tissue. This degenerative or adaptative cellular process was characterized mainly by marked proliferation of the cytoskeleton and a general loss of organelles, mitochondria being the least affected.