The present study aimed to evaluate the suitability of Smopex-102 cation-exchange fiber for the separation of acidic and basic model drugs from biological fluids (e.g. serum) prior to chromatographic analysis. In addition, the interactions of the drugs with the fiber were studied. The study found that basic antidepressant model drugs bound to a considerably greater extent than acidic drugs to poly(acrylic acid) (PAA) grafted Smopex-102 cation-exchange fiber from 25 mM HEPES buffer (pH 7.0) and spiked serum. Drug binding from serum decreased except for acidic drugs due to drug distribution between serum proteins and cation-exchange fiber. Electrostatic interactions were possibly the most important factors affecting drug binding to the fiber. Basic drugs were released most effectively from the fiber by using acetic acid (mean released amount 123.7 +/- 36.3% and mean absolute recovery 95.4 +/- 23.8%). Results demonstrated that the cation-exchange fiber evaluated might be a potential material for separating basic drugs from protein-free and proteinaceous (e.g. serum) liquid solutions for subsequent monitoring and evaluation. However, the drug release solution and release time must be optimized more precisely in order to validate described sample preparation method for each basic drug.