Context: Patients with cancer often have other medical ailments, referred to as comorbidity. Comorbidity may impact treatment decision-making, prognosis, and quality of care assessment. Objective: To assess whether comorbidity information can provide important prognostic information in a hospital-based cancer registry. Design, Setting, and Participants: An observational prospective cohort study using comorbidity data collected by trained hospital-based cancer registrars. Comorbidity was obtained through medical record review using the Adult Comorbidity Evaluation 27, a validated chart-based comorbidity instrument. A total of 17 712 patients receiving care between January 1, 1995, and January 31, 2001, for the primary diagnosis of new cancer of the prostate, lung (nonsmall cell), breast, digestive system, gynecological, urinary system, or head and neck were included. Main Outcome Measure: Duration in months of overall survival. Results: A total of 19268 patients were included in the study; median duration of follow-up was 31 months. Of these patients, 1556 (8.0%) were excluded due to missing or unknown data. Severity of comorbidity strongly influenced survival in a dose-dependent fashion and the impact of comorbidity was independent of cancer stage. Compared with patients without comorbidity, the adjusted hazard ratio associated with mild comorbidity was 1.21 (95% confidence interval [CI], 1.13-1.30), moderate comorbidity was 1.86 (95% CI, 1.73-2.00), and severe comorbidity was 2.56 (95% CI, 2.35-2.81). Adjusted Kaplan-Meier survival curves revealed that at any point in time the patients with more severe levels of comorbidity had worse survival (partial χ32 due to comorbidity, 523.54; P<.001). Model discrimination ranged from 0.71 for head and neck to 0.86 for prostate cancers. Conclusions: Comorbidity is an important independent prognostic factor for patients with cancer. The inclusion of comorbidity in hospital-based cancer registries will increase the value and use of observational research.