Objective To compare alternative strategies for specifying cancer‐free control cohorts for estimating cancer‐attributable costs of care. Data Source, Study Design, Data Extraction Secondary data analysis of Surveillance, Epidemiology, and End Results data linked to Medicare claims among patients diagnosed with colorectal, lung, breast, and prostate cancers, 2007–2011. We estimated cancer‐attributable costs using three alternative reference cohorts: (1) noncancer Medicare patients individually matched by demographic characteristics, (2) noncancer patients individually matched on demographic factors and comorbidity score, (3) cancer patients as their own control, using prediagnosis costs. Principal Findings Among 44,266 colorectal, 61,584 lung, 55,921 breast, and 67,733 prostate patients, mean total Medicare spending in the first year of diagnosis was $59,496, $54,261, $31,895, and $26,305, respectively. Estimates of cancer‐attributable costs ranged from 79 percent to 82 percent of spending for colorectal, 76 percent–79 percent for lung, 65 percent–74 percent for breast, and 60 percent–75 percent for prostate cancers, depending on the reference cohort used. For all cancers, estimates were higher when patients were used as their own control, compared to demographic and comorbidity‐matched controls. Conclusions Choice of reference group can have a substantial impact on proportion of total costs attributed to cancer and should be clearly defined in analyses of the costs of cancer care.