The objective of this work was the synthesis of serum albumin targeted, GdIII-based magnetic resonance imaging (MRI) contrast agents exhibiting a strong pH-dependent relaxivity. Two new complexes (Gd-glu and Gd-bbu) were synthesized based on the DO3A macrocycle modified with three carboxyalkyl substituents a to the three ring nitrogen atoms, and a biphenylsulfonamide arm. The sulfonamide nitrogen coordinates the Gd in a pH-dependent fashion, resulting in a decrease in the hydration state, q, as pH is increased and a resultant decrease in relaxivity (r1). In the absence of human serum albumin (HSA), r1 increases from 2.0 to 6.0 mM-1?s-1 for Gd-glu and from 2.4 to 9.0 mM-1?s-1 for Gd-bbu from pH 5 to 8.5 at 37?degrees C, 0.47 T, respectively. These complexes (0.2 mM) are bound (>98.9?%) to HSA (0.69 mM) over the pH range 58.5. Binding to albumin increases the rotational correlation time and results in higher relaxivity. The r1 increased 120?% (pH 5) and 550?% (pH 8.5) for Gd-glu and 42?% (pH 5) and 260?% (pH 8.5) for Gd-bbu. The increases in r1 at pH 5 were unexpectedly low for a putative slow tumbling q=2 complex. The Gd-bbu system was investigated further. At pH 5, it binds in a stepwise fashion to HSA with dissociation constants Kd1=0.65, Kd2=18, Kd3=1360 mu M. The relaxivity at each binding site was constant. Luminescence lifetime titration experiments with the EuIII analogue revealed that the inner-sphere water ligands are displaced when the complex binds to HSA resulting in lower than expected r1 at pH 5. Variable pH and temperature nuclear magnetic relaxation dispersion (NMRD) studies showed that the increased r1 of the albumin-bound q=0 complexes is due to the presence of a nearby water molecule with a long residency time (12 ns). The distance between this water molecule and the Gd ion changes with pH resulting in albumin-bound pH-dependent relaxivity.