Background: Prominent studies continue to measure the hospital volume-outcome relation using simple logistic or random-effects models. These regression models may not appropriately account for unobserved differences across hospitals (such as differences in organizational effectiveness) which could be mistaken for a volume outcome relation. Objective: To explore alternative estimation methods for measuring the volume-outcome relation for six major cancer operations, and to determine which estimation method is most appropriate. Methods: We analyzed patient-level hospital discharge data from three USA states and data from the American Hospital Association Annual Survey of Hospitals from 2000 to 2011. We studied six major cancer operations using three regression frameworks (logistic, fixed-effects, and random-effects) to determine the correlation between patient outcome (mortality) and hospital volume. Results: For our data, logistic and random-effects models suggest a non-zero volume effect, whereas fixed-effects models do not. Model-specification tests support the fixed-effects or random-effects model, depending on the surgical procedure; the basic logistic model is always rejected. Esophagectomy and rectal resection do not exhibit significant volume effects, whereas colectomy, pancreatic resection, pneumonectomy, and pulmonary lobectomy do.