• We examined the effect of topically applied 3 - isobutyl - 1 - methylxanthine (IBMX), a known secretagogue, on tear secretion and dry-eye disease in a clinical study. We found that IBMX produced a dose-dependent decrease in tear film osmolarity that was significant at 3.0 mmol/L (P<.0005) in patients with dry-eye disease. This effect was not blocked by prior administration of proparacaine hydrochloride (P<.05). Throughout a 4-week, open-label, vehicle-controlled study, IBMX decreased tear film osmolarity significantly, whereas vehicle alone did not. After 4 weeks, mean (±SEM) osmolarity in IBMX-treated eyes decreased from 325±3.2 mOsm/L to 312±1.8 mOsm/L but remained unchanged in vehicle-treated eyes (323±4.4 mOsm/L vs 320±4.2 mOsm/L). In our study, IBMX was significantly more effective than vehicle alone in decreasing rose bengal staining (P<.02). Hence, topical IBMX stimulated tear secretion and decreased ocular surface disease in patients with dry-eye disease.