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After long-duration spaceflight, morphological changes in the optic nerve head (ONH) and surrounding tissues have been reported.To develop methods to quantify ONH and surrounding tissue changes using preflight and postflight optical coherence tomographic scans of the ONH region.Two separate analyses were done on retrospective data, with the first comparing a preflight group with a control group, followed by preflight to postflight analysis. All astronaut data were collected on the same instrument and maintained by the National Aeronautics and Space Administration (NASA) Lifetime Surveillance of Astronaut Health. Control data were all collected at the University of Houston. Participants were 15 astronauts who had previously been on an approximately 6-month long-duration mission and had associated preflight and postflight ONH scans. The control group consisted of 43 individuals with no history of ocular pathology or microgravity exposure. Development of algorithms and data analysis were performed between 2012 and 2015.The optical coherence tomography data were analyzed using custom MATLAB programs (MathWorks) in which the Bruch membrane opening (BMO) was manually delineated and used as a reference for all morphological measures. The retinal pigment epithelium (RPE) position 2 mm from the center of the BMO was used to calculate the BMO height. Global and quadrant total retinal thickness and retinal nerve fiber layer (RNFL) thickness were calculated for elliptical annular regions referenced to the BMO. The standard circumpapillary circular scan was used to quantify RNFL and choroidal thickness.Among 15 astronauts (mean [SD] age at preflight evaluation, 48.7 [4.0] years) in this retrospective study, the BMO was recessed in preflight astronauts compared with healthy controls and deepened after long-duration microgravity exposure (median change, −9.9 μm; 95% CI of difference, −16.3 to 3.7 μm; P = .03). After long-duration missions, there was an increase in total retinal thickness to 1000 μm and RNFL to 500 μm from the BMO. Circumpapillary RNFL thickness increased by a median of 2.9 μm (95% CI of difference, 1.1-4.4 μm; P < .01), and there was no change in choroidal thickness (median change, 9.3 μm; 95% CI of difference, −12.1 to 19.6 μm; P = .66).After long-duration microgravity exposure, there are disc edema–like changes in the morphology of the ONH and surrounding tissue. The methods developed to analyze the ONH and surrounding tissue can be useful for assessing longitudinal changes and countermeasures in astronauts, as well as potentially for terrestrial disc edema causes.