After working at Oak Ridge National Laboratory and later the Centers for Disease Control, Calle joined the American Cancer Society (ACS) in 1989 as the director of their Study Management Group.[2] She became the director of Analytic Epidemiology in Epidemiology and Surveillance at the ACS in 1999, and was later promoted to Vice President of Epidemiology there.[2] While at the ACS, she directed the Cancer Prevention Study, and also conducted two landmark studies on the link between obesity and cancer.[3] Roughly two weeks before her death, Calle retired as Vice President of Epidemiology and Surveillance Research at the ACS.[3]