Since the 1970s, significant QX disease outbreaks have taken place in Sydney rock oyster (Saccostrea glomerata)producing estuaries in New South Wales, Australia, devastating production. Despite research efforts, there are still many gaps in our knowledge of QX disease (causative agent: Marteilia sydneyi). A better understanding of the timing and triggers of the QX infection would allow the management of oyster farms to be tailored to address the high-risk period. This study examined the extent and variability of the QX window of infection across multiple years (2005/2006 to 2008/2009) in the Hawkesbury River and characterized environmental conditions prior to, during, and after the infection window during these years. The window of QX infection onset across the years was found to be highly variable, with start times occurring between November and February, whereas the infection termination time was more defined, occurring within the first week in April, except in 2006/2007, which ceased during the last week of April. The termination of the infection window occurred during a significant decrease in water temperature (at a rate of 3.7°C/mo), with no infection occurring at water temperatures less than 21.5°C Environmental conditions were more variable at the onset of the infection window, when water temperatures showed high levels of variability among years as a result of cool freshwater inputs from rainfall events, which occur commonly at this time of year. These freshwater inputs also resulted in significant decreases in salinity levels (to at least ∼10 ppt), which may be an additional factor influencing QX disease outbreaks. Previous QX work suggested an infection period of 19 days; here, longer infection periods were observed and lasted between 8 wk and 18 wk, depending on the year.