BACKGROUND: Involuntary weight loss (IWL) is a frequent complaint with a difficult diagnosis. Any one of a number of different diseases may be the source of the symptom. However, there is no universal clinical protocol that can help physicians study this complex syndrome. METHODS: In March 1998, we defined a diagnostic protocol for the study of IWL. IWL was defined as an involuntary and documented weight loss of at least 5% of the usual body weight in the previous 3 months. We analyzed 78 consecutive patients with IWL who came to our clinic between March 1998 and December 2000. RESULTS: An organic disease was found in 56% of cases; cancer, metabolic and digestive diseases were the most common entities. Psychiatric problems were found in 33% of cases. After extensive study, an idiopathic group of 11% was identified. The variables that were independently predictive of a final diagnosis of organic disease were: age>50 years (OR: 8.6, CI 95%: 1.7-43.6), psychiatric symptoms (OR: 0.2, CI 95%: 0.1-0.8), smoking (OR: 14.3, CI 95% 2.3-74), the presence of guide symptoms (OR: 8.0, CI 95%: 1.8-34.4), and anemia (OR: 3.1, CI 95%: 2.5-387). Sixteen percent of the patients died, more often those suffering from organic diseases. Based on multivariate regression coefficients, a clinical risk score was established. CONCLUSIONS: IWL is a complex and frequent syndrome with a 16% rate of mortality during the first year. A protocol based on clinical data can help in the management of IWL. Our clinical prediction rule may help physicians to identify those patients with IWL who are likely to have an underlying organic disease.