Disease clusters have been an important source of epidemiologic and medical information in the history of occupational medicine. Many accepted disease-exposure linkages were first observed and investigated as disease clusters in the workplace setting. Recent interest in disease cluster methodology has focused on traditional environmental settings. There has been very little work on a similar methodology for the investigation of disease clusters in the workplace, despite the many advantages of workplace cluster investigations for recognizing new etiologic associations. In this paper, a protocol is proposed and discussed which can be implemented in both acute and chronic disease cluster outbreaks in the workplace, where no obvious previously recognized cause is identified. A standardized approach to occupational disease cluster investigation will lead to increased efficiency, decreased social-political tensions, and a greater yield of scientific information.