OBJECTIVE: Currently, the only available staging criterion for T. b. rhodesiense requires a lumber puncture to collect and later examine cerebrospinal fluid (CSF). This study examined the potential of plasma Neuron-Specific Enolase (NSE) in discriminating between early and late-stage patients. RESULTS: When median NSE levels were compared between early and late-stage patients, results showed a significant (Pâ<â0.02) upregulation among late-stage patients (599.8Â ng/mL). No significant differences (Pâ>â0.9) in NSE levels were observed between early-stage patients (300Â ng/mL) and controls (454Â ng/mL). We used Receiver Operator Characteristic (ROC) curves to explore the likelihood of using plasma NSE as a potential stage biomarker in discriminating between early and late-stage HAT patients. Our results showed that NSE demonstrated an area under the curve (AUC) of 0.702 (95% CI 0.583-0.830). A high staging accuracy for NSE was obtained by using a cutoff ofâ>â346.5Â ng/mL with a sensitivity of 68.6% (95% CI 55-79.7%) and a specificity of 93.3% (95% CI 70.2-99.7%). Although our results demonstrate that plasma NSE is upregulated in T. b. rhodesiense sleeping sickness patients, its value in discriminating between late and early-stage patients is limited. However, future studies could consider improving its specificity by combining it with other identified plasma biomarkers.