Poly(2-isopropenyl-2-oxazoline) (PiPOx) is emerging as a promising, versatile polymer platform to design functional materials and particularly biomaterials that rely on the hydrophilic character of the 2-oxazoline side units. To be able to assess the applicability of PiPOx in a biomedical context, it is essential to understand its stability and degradation behavior in physiological conditions. In the present work, the hydrolytic stability of PiPOx was systematically investigated as a function of pH during incubation in various buffers. PiPOx was found to be stable in deionized water (pH 6.9), to have good stability in basic conditions (pH 8 and 9), to be satisfactorily stable in neutral conditions (pH 7.4), and to have moderate to low stability in acidic conditions (decreases drastically from pH 6 to pH 1.2). At pH 4, PiPOx formed a crosslinked network in a timeframe of hours, while at pH 1.2, PiPOx was transformed to a water-soluble poly(N-(2-hydroxyethyl)methacrylamide) type of structure over the course of 2 weeks. In vitro stability assays were performed in phosphate-buffered saline (pH 7.4), simulated body fluid (SBF) (pH 7.4), simulated saliva (pH 6.4), simulated intestinal fluid (pH 6.8), and plasma (pH 7.4) revealing that PiPOx is stable in these SBFs up to 1 week of incubation. When incubated in simulated gastric fluid (pH 1.2), PiPOx exhibited a similar degradation behavior to that observed in the buffer at pH 1.2, rendering a water-soluble structure. The presented results on the stability of PiPOx will be important for future use of PiPOx for the development of drug-delivery systems and biomedical applications, such as hydrogels.