Buccal delivery of saquinavir has the advantage to bypass the hepatic first-pass metabolism associated with oral administration. Local microenvironmental pH (pH_M) modification at the buccal mucosa might increase absorption of saquinavir by balancing the solubility and partition of saquinavir into the buccal mucosa. The present study aimed to evaluate a novel saquinavir pH_M modifying buccal film using effervescence, as well as to elucidate the relationship between pH_M and permeation of saquinavir released from the buccal films. Hydroxypropyl methylcellulose-based films were prepared: 1) a bilayered effervescent film composed of an alkaline layer and a layer containing saquinavir and malic acid, 2) a monolayered film composed of saquinavir and malic acid (pH_M modifying film), and 3) a monolayered film composed of saquinvir (control). The release of saquinavir from these films and permeation of saquinavir across porcine mucosae were evaluated. The monolayered pH_M modifying film led to a decrease in pH_M from pH 6.8 to 3.0 after 5.5 min, while the effervescent film had an initial decrease in pH_M (from pH 6.8 to 4.0) caused by the co-release of malic acid and a subsequent pH_M increase (from pH 4.0 to 5.9) caused by the release of carbonate from the alkaline layer within 15 min. Saquinavir released faster from the pH_M modifying film than from the effervescent film. However, a higher permeation of saquinavir and mucosal accumulation was observed for the effervescent film. This could be attributed to the higher concentration of ionized specie and a faster tissue partitioning of unionized saquinavir, respectively. These results suggest that effervescent pH_M modifying film is a potential formulation strategy for buccal delivery of saquinavir.