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The tumor microenvironment is characteristically acidic and this extracellular acidosis is known to play a role in carcinogenesis and metastasis and can affect tumor chemosensitivity and radiosensitivity. Intracellular pH has been used as a possible biomarker of salvageable tissue in ischemic stroke. A non-invasive MRI-based approach for the determination and imaging of cerebral pH would be a powerful tool in cancer diagnosis and monitoring, as well as stroke treatment planning. Several pH-based MRI imaging approaches have been proposed but for these to be useful, disentangling the effects of pH from other parameters which may affect the measured MRI signal is crucial to ensure accuracy and specificity. R1 relaxation in the rotating frame (R1ρ) is an example of a method that has been proposed to probe pH in vivo using MRI. In this study, we have investigated the relationship between R1ρ, pH, and macromolecular density in vitro using phantoms and in human volunteers. Here we show that the rate of R1ρ relaxation (=1/T1ρ) varies with pH but only in the presence of macromolecules. At constant pH, phantom macromolecular density inversely correlated with R1ρ. R1ρ imaging of the normal human brain demonstrated regional heterogeneity with significant differences between structurally distinct regions, which are likely to be independent of pH. For example, R1ρ was higher in the basal ganglia compared to grey matter and higher in grey matter compared to white matter. We conclude that R1ρ cannot be reliably used to image tissue pH without deconvolution from the effects of local tissue macromolecular composition.