Importance There are limited means to predict which crewmembers are at risk for developing optic disc edema (ODE) during spaceflight. Identifying crewmembers who have a low probability of developing ODE will allow for reduced monitoring and countermeasure resources, thereby enabling alternate mission activities. Objective To determine if magnitude of ODE early in flight is associated with magnitude of ODE later in flight. Design, Setting, and Participants This cohort study involved crewmembers on board the International Space Station. Participants were astronauts who had optical coherence tomography (OCT) imaging before, during, after their spaceflight mission. Preflight and in-flight total retinal thickness (TRT) was quantified within the annular region from Bruch membrane opening to 250 μm using OCT. The change (Δ) in TRT is an objective approach to quantifying ODE. Exposure Spaceflight missions lasting approximately 6 months long. Main Outcomes and Measures Preflight to in-flight ΔTRT. Data were analyzed using linear and log-binomial mixed effects models to determine (1) if ΔTRT on flight day (FD) 30 was associated with ΔTRT on FD150 and (2) the probability a crewmember with ΔTRT less than 20 μm on FD30 would exhibit ΔTRT less than 55 μm on FD150 or a crewmember with ΔTRT of 20 of 55 μm on FD30 would develop ΔTRT greater than 55 μm on FD150. Results Data from 43 ISS crewmembers (mean [SD] age, 47 [7] years; 35 males [81%] and 8 females [19%]) with a mean (SD) flight duration of 198 (55) days were included. There was an association between FD30 ΔTRT and FD150 ΔTRT (repeated-measure correlation coefficient = 0.89; 95% CI, 0.80-0.94; P &lt; .001). Eyes with ΔTRT less than 20 on FD30 had 2% probability (95% CI, 1%-15%) of ΔTRT of 55 μm or greater on FD150. Receiver operating curve analysis determined an optimal threshold ΔTRT of greater than 29 μm on FD30 to distinguish eyes at risk of ΔTRT of 55 μm or greater on FD150. Eyes with ΔTRT of 20 to 55 μm or 29 to 55 μm on FD30 had a 34% (95% CI, 19%-60%) or 58% (95% CI, 37%-90%) probability, respectively, of ΔTRT of 55 μm or greater on FD150. Conclusions and Relevance Findings suggest crewmembers who did not develop ODE on FD30 were unlikely to develop clinically concerning ODE on FD150. The data suggest that OCT imaging during spaceflight missions provides an opportunity to predict the magnitude of ODE that may develop during a longer-lasting mission.