The effects of biological buffers on lipids have not been fully investigated because of the long-standing assumption that these buffers are too hydrophilic to substantially interact with the lipid membrane. We present evidence that for some buffers, this is not necessarily the case. Our research points toward a membrane softening effect caused by the buffer molecules interacting with the headgroup region of the lipid. Changes in the elastic properties of the membrane are known to control membrane protein behavior; this work serves as a warning for the design of assays utilizing model membranes in the presence of buffers.