The objectives of this study were to establish an in-depth understanding of the signals induced by mammalian cells in surface plasmon resonance (SPR) sensing. To this end, two plasmonic structures with different propagation and penetration distances were used: conventional surface plasmon resonance and long-range surface plasmon resonance. Long-range SPR showed a lesser sensitivity to the absolute number of round cells but a greater resolution due to its very narrow spectral dip. The effect of cell spreading was also investigated and the resonance angle of long-range SPR was mostly insensitive unlike in the conventional SPR counterpart. Experimental data was compared with suitable models used in the SPR literature. Although these simple averaging models could be used to describe some of the experimental data, important deviations were observed which could be related to the fact that they do not take into consideration critical parameters such as plasmon scattering losses, which is particularly crucial in the case of long-range SPR structures. The comparison between conventional and long-range SPR for cellular schemes revealed important fundamental differences in their responses to the presence of cells, opening new horizons for SPR-based cell assays. From this study, long-range SPR is expected to be more sensitive towards both the detection of intracellular events resulting from biological stimulation and the detection of microorganisms captured from complex biological samples.