Importance – There is limited information on the association among complementary medicine (CM), adherence to conventional cancer treatment (CCT), and overall survival of patients with cancer who receive CM compared with those who do not receive CM. Objectives – To compare overall survival between patients with cancer receiving CCT with or without CM and to compare adherence to treatment and characteristics of patients receiving CCT with or without CM. Design, Setting, and Participants – This retrospective observational study used data from the National Cancer Database on 1 901 815 patients from 1500 Commission on Cancer–accredited centers across the United States who were diagnosed with nonmetastatic breast, prostate, lung, or colorectal cancer between January 1, 2004, and December 31, 2013. Patients were matched on age, clinical group stage, Charlson-Deyo comorbidity score, insurance type, race/ethnicity, year of diagnosis, and cancer type. Statistical analysis was conducted from November 8, 2017, to April 9, 2018. Exposures Use of CM was defined as “Other-Unproven: Cancer treatments administered by nonmedical personnel” in addition to at least 1 CCT modality, defined as surgery, radiotherapy, chemotherapy, and/or hormone therapy. Main Outcomes and Measures Overall survival, adherence to treatment, and patient characteristics. Results – The entire cohort comprised 1 901 815 patients with cancer (258 patients in the CM group and 1 901 557 patients in the control group). In the main analyses following matching, 258 patients (199 women and 59 men; mean age, 56 years [interquartile range, 48-64 years]) were in the CM group, and 1032 patients (798 women and 234 men; mean age, 56 years [interquartile range, 48-64 years]) were in the control group. Patients who chose CM did not have a longer delay to initiation of CCT but had higher refusal rates of surgery (7.0% [18 of 258] vs 0.1% [1 of 1031]; P < .001), chemotherapy (34.1% [88 of 258] vs 3.2% [33 of 1032]; P < .001), radiotherapy (53.0% [106 of 200] vs 2.3% [16 of 711]; P < .001), and hormone therapy (33.7% [87 of 258] vs 2.8% [29 of 1032]; P < .001). Use of CM was associated with poorer 5-year overall survival compared with no CM (82.2% [95% CI, 76.0%-87.0%] vs 86.6% [95% CI, 84.0%-88.9%]; P = .001) and was independently associated with greater risk of death (hazard ratio, 2.08; 95% CI, 1.50-2.90) in a multivariate model that did not include treatment delay or refusal. However, there was no significant association between CM and survival once treatment delay or refusal was included in the model (hazard ratio, 1.39; 95% CI, 0.83-2.33). Conclusions and Relevance – In this study, patients who received CM were more likely to refuse additional CCT, and had a higher risk of death. The results suggest that mortality risk associated with CM was mediated by the refusal of CCT.