Alginate-poly-L-lysine (PLL) microencapsulation of cells is a promising approach to prevent rejection in the absence of immunosuppression. Clinical application, however, is hampered by insufficient insight in factors influencing biocompatibility of the capsules. By now, it has been accepted that not only the chemical composition of the materials applied but also other factors contribute to bioincompatibility. The zeta-potential serves as a measure for the electrical charge of the surface and has been shown to be a predictive value for the interfacial reactions between the biomaterial and the surrounding tissue in other applications. In the present study, we have assessed the streaming potential of alginate-PLL capsules composed of either low-, intermediate-, or high-guluronic (G) alginate to calculate the zeta-potential. The zeta-potentials of the capsules were compared to the biological response against the capsules at 4 weeks after implantation in the rat. We show that high-G and low-G alginates provoke a more severe response in the rat than capsules prepared of intermediate-G alginate. This correlates with a higher zeta-potential of the high-G and low-G alginates and by a change in zeta-potential at lower pH. These lower pH-levels are common directly after implantation as the consequence of a host-response associated with mandatory surgery. Our results suggest that we should not only consider the capsule properties under physiological circumstances to explain bioincompatibility but also the capsule features during common pathophysiological situations.