Different case definitions of schizophrenia have been used in register based research. However, no previous study has externally validated two different case definitions of schizophrenia against a wide range of risk factors for schizophrenia. We investigated hazard ratios (HRs) for a wide range of risk factors for ICD-10 DCR schizophrenia using a nationwide Danish sample of 2,772,144 residents born in 1955-1997. We compared one contact only (OCO) (the case definition of schizophrenia used in Danish register based studies) with two or more contacts (TMC) (a case definition of at least 2 inpatient contacts with schizophrenia). During the follow-up, the OCO definition included 15,074 and the TMC 7562 cases; i.e. half as many. The TMC case definition appeared to select for a worse illness course. A wide range of risk factors were uniformly associated with both case definitions and only slightly higher risk estimates were found for the TMC definition. Choosing at least 2 inpatient contacts with schizophrenia (TMC) instead of the currently used case definition would result in almost similar risk estimates for many well-established risk factors. However, this would also introduce selection and include considerably fewer cases and reduce power of e.g. genetic studies based on register-diagnosed cases only.