Based on results from the Belgian External Quality Assessment (EQA) Scheme, we studied the main factors affecting the between-laboratory variation of C-reactive protein determination. Participants using homogeneous systems with several calibration points generally achieved better performance. Working temperatures influenced the results to a lesser extent. The present study stresses the importance for EQA organizers to collect more detailed information about CRP analytical methods used by the participants. It also suggests that manufacturers should be more involved in the management of quality, in particular by striving for standardization of the material (kit and calibrator) they produce for CRP assay.