This study followed workers over an extended period of time to identify factors which may influence the onset of Carpal Tunnel Syndrome (CTS). The purpose was to evaluate incidence of CTS and to create a predictive model of factors that play a role in the development of CTS. This prospective study followed 432 industrial and clerical workers over 5.4 years. Incident cases were defined as workers who had no prior history of CTS at baseline testing and were diagnosed with CTS during the follow-up period or at the follow-up screening. On the basis of logistic regression, significant predictors for CTS include baseline median-ulnar peak latency difference, a history of wrist/hand/finger tendonitis, a history of numbness, tingling, burning, and/or pain in the hand, and work above the action level of the peak force and hand activity level threshold limit value. This longitudinal study supports findings from previous cross-sectional studies identifying both work related ergonomic stressors and physical factors as independent risk factors for CTS.