Background The current study explores how sex and age relate to biopsychosocial distress by applying a large‐scale analysis among individuals diagnosed with a variety of cancers. Methods A retrospective study was conducted involving 6462 patients treated for cancer at a National Cancer Institute‐designated comprehensive cancer center between 2009 and 2014. Patients were asked to complete the biopsychosocial problem‐related distress touchscreen instrument prior to starting treatment as part of their routine clinical care. Results There was a significant interaction of age and sex on the total number of problems rated as high distress and the total number of problems that prompted a request to talk with a member of the team. Male patients between 18 and 39 reported significantly more problems as high distress than female patients in the same age group (mean = 5.34 and mean = 4.92, respectively; p = 0.005). A similar trend was found where male patients between 18–39 and 40–64 requested to talk with a member of the team significantly more often than female patients in these same age groups (mean = 3.25 and mean = 3.22 vs. mean = 2.70 and mean = 3.07, respectively; p = 0.016). Conclusions The results of the current study serve to refute generalizations regarding age or gender demographics and support preferences and thus reinforce the need to offer services in the context of cancer in flexible and varied ways. Copyright © 2016 John Wiley & Sons, Ltd.