In vivo forming hydrogels are of interest for diverse biomedical applications due totheir ease-of-use and minimal invasiveness and therefore high translational potential. Supramolecular hydrogels that can be assembled usingmetal–phenolic coordination of naturally occurring polyphenols and group IV metal ions (e.g. TiIVor ZrIV) provide a versatile and robust platform for engineering such materials. However, the in situformation and in vivoresponse tothis new class of materials has not yet been reported. Here, we demonstrate that metal–phenolic supramolecular gelation occurs successfully in vivo and we investigate the host response to the material over 14 weeks. TheTiIV–tannic acid materials form stable gels that are well-tolerated following subcutaneous injection. Histology reveals a mild foreign body reaction, and titanium biodistribution studies show low accumulation in distal tissues. Compared to poloxamer-based hydrogels (commonly used for in vivogelation), TiIV–tannic acid materials show a substantially improved in vitrodrug release profile for the corticosteroid dexamethasone (from <1 dayto >10 days). These results provide essential in vivo characterization for this new class of metal–phenolic hydrogels, and highlight their potential suitability for biomedical applications in areas such as drug deliveryand regenerative medicine