A series of studies was performed to investigate some of the causes for matrix effects ('ion suppression' or 'ion enhancement') in bioanalytical high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS) assays. Previous studies have reported that matrix effects are mainly due to endogenous components in biological fluids and are a greater concern for electrospray ionization (ESI) than for atmospheric pressure chemical ionization (APCI). In this report we demonstrate that: (1) matrix effects can also be caused by exogenous materials, such as polymers contained in different brands of plastic tubes, or Li-heparin, a commonly used anticoagulant; (2) matrix effects are not only ionization mode (APCI or ESI) dependent, but also source design (Sciex, Finnigan, Micromass) dependent; and (3) for at least one vendor's design, we found the APCI mode to be more sensitive to matrix effects than the ESI mode. Based on these findings, we have proposed the following simple strategies to avoid matrix effects: (1) select the same brand of plastic tubes for processing and storing plasma samples and spiked plasma standards; (2) avoid using Li-heparin as the anticoagulant; and (3) try switching the ionization mode or switching to different mass spectrometers when matrix effects are encountered. These three strategies have allowed us to use protein precipitation and generic fast LC techniques to generate reliable LC/MS/MS data for the support of pharmacokinetic studies at the early drug discovery stage.