Importance Spaceflight-associated neuro-ocular syndrome (SANS) could severely impact astronaut performance during long-duration spaceflight (LDSF). The pathophysiology of SANS remains elusive, and no predictors of SANS have been discovered; reliable prediction may offer novel insight into individual susceptibility and interperson variability for SANS and permit prelaunch preparations for in-flight treatment. Objective To conduct a preliminary analysis of SANS flight data to determine mission-to-mission trends in SANS diagnosis and optic disc edema (ODE) severity. Design, Setting, and Participants In this cohort study, ocular testing, including optical coherence tomography (OCT), was completed preflight, during flight, and postflight, then retrospectively analyzed in a unique cohort of US National Aeronautics and Space Administration (NASA) astronauts who completed 2 LDSF missions onboard the International Space Station (ISS) from 2007 to 2024. Data were analyzed from April 2024 to April 2025. Exposure Weightlessness, with average durations of 6 months for each mission. Main Outcomes and Measures The primary outcome was SANS or non-SANS diagnosis, determined by OCT-based ODE data (when available after 2013) for each mission. Results Of 71 NASA astronauts who have participated in ISS LDSF, 16 (22.5%) have completed 2 long-duration missions. Four astronauts (20%) were female, and mean ages of astronauts participating in missions 1 and 2 were 46.1 (4.0) and 53.5 (5.2) years, respectively. For these 16 individuals, a SANS diagnosis or nondiagnosis from prior LDSF predicted SANS diagnosis during subsequent LDSF (sensitivity, 85.7%; 95% CI, 42%-100%; specificity, 100%; 95% CI, 66%-100%; positive predictive value, 100%, 95% CI, 54%-100%; negative predictive value, 90%; 95% CI, 56%-100%; P &lt; .001). A subset of this group (5 participants, 10 eyes) possessed an objective metric of ODE across both missions (ie, change in peripapillary total retinal thickness within 250 µm of Bruch membrane opening [ΔTRT]). For individual eyes, ΔTRT of a prior LDSF mission was highly predictive of ΔTRT for a subsequent LDSF ( r = 0.94; P &lt; .001). Conclusions and Relevance In this cohort study, SANS cases from previous LDSF were highly likely to be diagnosed with SANS in subsequent LDSF missions and vice versa, while SANS ODE severity appeared remarkably similar across LDSF missions for individual eyes. To our knowledge, these findings represent the first and only reliable forecast for SANS, permitting precise in-flight treatment and prevention strategies to be tailored for individual astronauts in subsequent LDSF missions, even before launch.