The phase behavior of model polymer-colloid mixtures is measured for solutions approaching the "protein limit", that is, when the radius of gyration of the polymer (Rg) is greater than or approximately equal to the radius of the colloid (R). Cationic nanoparticles are mixed with poly(ethylene oxide) (PEO) or poly(vinyl pyrolidone) (PVP) at size ratios of Rg/R = 0.7 and 1.8. The addition of PEO to stable nanoparticle dispersions leads to depletion flocculation in both deionized water and buffer solutions. The instability mechanism for the PVP-nanoparticle system depends on the suspension medium. In water, bridging occurs below the saturation adsorption of PVP, whereas depletion phase separation is evident at concentrations exceeding those necessary to saturate the particle surface. In acidic buffer, PVP addition results in depletion phase separation. The difference between bridging and depletion is distinguished by both visual appearances and rheological measurements. There is no trend (within error bars) in the polymer concentration required to induce instability with increasing Rg/Rin contrast with theoretical predictions. This is most likely due to adsorption of polymer onto the particle surface.