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Purpose To determine the in vivo effect of doxycycline (doxy) on choroidal angiogenesis and pterygium growth by using a choroidal neovascular murine model (CNV), a directed in vivo angiogenesis assay (DIVAA) and a pterygium murine model. Design Experimental Study Participants 3 murine models were investigated with 4 mice minimum per group and 22 maximum per group. Methods Mice received water with or without doxycycline (Leiter's Pharmacy, San Jose, CA). For the CNV, the neovascular lesion volume was determined in choroid-retinal pigment epithelial (RPE) flat mounts using confocal microscopy seven days after laser induction. For DIVAA, silicone capsules containing 10,000 human pterygium epithelial cells were implanted in the flanks of mice subcutaneously. After eleven days, neovascularization (NV) was quantified using spectrofluorimetry after murine tail-vein injection of fluorescein isothiocyanate (FITC)-labeled dextran. A pterygium epithelial cell model was developed by injecting 10,000 human pterygium epithelial cells in the nasal subconjunctival space in athymic nude mice. Doxy was started on day six at 50 mg/kg/day; corneal lesions that resulted from the injections were compared at days six and fifteen. Main outcome measures Student's t-test was used to evaluate the data for the CNV and DIVAA models and histologic preparations were used to evaluate pterygia lesions. Results There was significantly less NV and lesion volume with doxy taken in drinking water versus plain water. With doxy treatment, the laser-induced CNV showed a maximal 66% decrease in choroidal blood vessel volume (p≤0.008) and the DIVAA showed a 30% reduction of blood vessel growth and migration (p<0.004). Histologic preparations demonstrated that pterygium cell lesions regressed when mice were administered doxy for 9 days. Conclusions Doxycycline significantly inhibited angiogenesis in three murine models. The most dramatic effect was found in the choroidal neovascularization model followed by the pterygia epithelial cell DIVAA model. The anterior segment pterygium model also showed regression histologically. This suggests that doxycycline may be successful as an adjunctive treatment for choroidal neovascularization and pterygia in humans; clinical trials would be necessary to determine if there is a benefit.