Studies showing that patients with cancer from rural areas have worse outcomes than their urban counterparts have relied on cancer population data and did not account for differences in access to care. Clinical trial patients receive protocol-directed care by design, so large clinical trial databases are ideal for examining the impact of rural vs urban residency on outcomes. To compare the geographic distribution and survival outcomes for rural vs urban patients with cancer treated in clinical trials. In this comparative effectiveness retrospective cohort analysis, 36 995 patients from all 50 states enrolled in 44 phase 3 and phase 2/3 SWOG (formerly the Southwest Oncology Group) treatment trials from January 1, 1986, to December 31, 2012, were examined. Seventeen different cancer-specific analysis cohorts were constructed. Data through January 30, 2018, were analyzed. Rural vs urban residency was defined using the Rural-Urban Continuum Codes developed by the US Department of Agriculture. Multivariate Cox regression was used to estimate the association of residency with overall survival, progression-free survival, and cancer-specific survival, controlling for major disease-specific prognostic factors and demographic variables and stratifying by study. Different definitions of rurality were examined. The distribution of rural vs urban patients by geographic region was described. Overall, 27.7% of patients were 65 years or older (range across 17 cohort analyses, 7.8%-74.5%), 40.3% were female in the non-sex-specific analyses (range across 17 cohort analyses, 28.1%-45.9%), and 10.8% were black (range across 17 cohort analyses, 1.9%-22.4%). Overall, 19.4% of patients (7184 of 36 995) were from rural locations. Rural patients were more likely to be aged 65 years or older (rural, 30.7% aged ≥65 years vs urban, 27.0% aged ≥65 years; difference, 3.7%; 95% CI, 2.5%-4.9%; P < .001), were less likely to be black (rural, 5.4% vs urban, 12.1%; difference, 6.7%; 95% CI, 6.1%-7.3%; P < .001), were similar with respect to sex (rural, 40.4% female vs urban, 39.7% female; difference, 0.6%; 95% CI, -1.4% to 2.6%; P = .53), and were well represented within major US geographic regions (West, Midwest, South, and Northeast). Clinical prognostic factors were similar. In multivariable regression, rural patients with adjuvant-stage estrogen receptor-negative and progesterone receptor-negative breast cancer had worse overall survival (hazard ratio, 1.27; 95% CI, 1.06-1.51; P = .008) and cancer-specific survival (hazard ratio, 1.26; 95% CI, 1.04-1.52; P = .02). No other statistically significant differences for overall, progression-free, or cancer-specific survival were found. Results were consistent regardless of the definition of rurality. Rural and urban patients with uniform access to cancer care through participation in a SWOG clinical trial had similar outcomes. This finding suggests that improving access to uniform treatment strategies for patients with cancer may help resolve the disparity in cancer outcomes between rural and urban patients.