Microgravity-induced bone loss increases urinary calcium excretion which increases kidney stone formation risk. Not all individuals show the same degree of increase in urinary calcium and some pre-flight characteristics may help identify individuals who may benefit from in-flight monitoring. In weightlessness the bone is unloaded, and the effect of this unloading may be greater for those who weigh more. We studied whether pre-flight body weight was associated with increased in-flight urinary calcium excretion using data from Skylab and the International Space Station (ISS). The study was reviewed and approved by the National Aeronautics and Space Administration (NASA) electronic Institutional Review Board (eIRB) and data were sourced from the Longitudinal Study of Astronaut Health (LSAH) database. The combined Skylab and ISS data included 45 participants (9 Skylab, 36 ISS). Both weight and day in flight were positively related to urinary calcium excretion. There was also an interaction between weight and day in flight with higher weight associated with higher calcium excretion earlier in the mission. This study shows that pre-flight weight is also a factor and could be included in the risk assessments for bone loss and kidney stone formation in space.