Clarithromycin (CLA) is an aminomacrolide antibiotic whose physical properties are fascinating and challenging. It has very poor solubility at neutral intestinal pH, but much better solubility under acidic conditions due to amine protonation. The improved solubility in an acid environment is confounded by the poor chemical stability of clarithromycin that is quite labile toward acid-catalyzed degradation. This creates a complex system under gastrointestinal (GI) conditions: dissolution in the stomach, degradation, potential for precipitation in the small intestine, and interplay with the formulation components. We report herein a study of amorphous solid dispersion (ASD) of CLA with carboxyl-containing cellulose derivatives, which have recently been shown to be excellent ASD matrices for maximizing oral bioavailability. This approach was intended to improve CLA solubility in neutral media while minimizing release in an acid environment, and thereby increase its uptake from the small intestine. Amorphous polymer/CLA nanoparticles were also prepared by high-shear mixing in a multi-inlet vortex mixer (MIVM). Different extents of release were observed at low pH from the various formulations. Thus the solubility increase from nanosizing was deleterious to the concentration of intact CLA obtained upon reaching small intestine conditions; the high extent of release at gastric pH led to complete degradation of CLA. Using pH-switch experiments, it was possible to separate the effects of loss of CLA from solution by crystallization vs. that from chemical degradation. It was found that the hydrophobic cellulose derivative cellulose acetate adipate propionate (CAAdP) was effective at protecting CLA from dissolution in the stomach, and preventing CLA decomposition at low pH; 54% of CLA in CAADP ASD was released intact, vs. 0% and 6% from HPMCAS and CMCAB ASDs, respectively. We conclude that protection against degradation is central to enhancing overall release of intact CLA from ASD formulations; the formulations studied herein have great promise for simultaneous CLA solubility enhancement and protection from loss to chemical degradation, thereby reducing dose requirements and potentially decreasing colonic exposure to CLA (reduced colonic exposure is expected to minimize killing of beneficial colonic bacteria by CLA).