Many cellular activities are controlled by post-translational modifications, the study of which is hampered by the lack of specific reagents, due in large part to their ubiquitous and non-immunogenic nature. Although antibodies against specifically modified sequences are relatively easy to obtain, it is extremely difficult to derive reagents recognizing post-translational modifications independently of the sequence context surrounding the modification. In this paper, we have examined the possibility of selecting such antibodies from large phage antibody libraries, using sulfotyrosine as a test case. Sulfotyrosine is a post-translational modification important in many extracellular protein-protein interactions, including HIV infection. After screening almost 8000 selected clones, we were able to isolate a single specific scFv, using two different selection stragies, one of which included elution with tyrosine sulfate. This antibody is able to recognize sulfotyrosine independently of its sequence context in test peptides and a number of different natural proteins. Antibody reactivity is lost by antigen treatment with sulfatase, or preincubation with soluble tyrosine sulfate, indicating its specificity. The isolation of this antibody signals the potential of phage antibody libraries in the derivation of reagents specific for post-translational modifications, although the extensive screening required indicates that such antibodies are extremely rare.