The local delivery and controllable release profiles make electrospun ultrafine fibers as potential implantable drug carriers and functional coatings of medical devices. Till date there is no literature report on drug delivery from acid-labile electrospun fibers, whose degradation and drug release behaviors respond to the local pathological pH environment. Acid-labile groups have been incorporated into nonbiodegradable backbones as crosslinkers or linkers of the side chains. A novel strategy was developed in this study to synthesize acid-labile polymers by introducing acetal groups into biodegradable backbone of poly(dl-lactide)-poly(ethylene glycol). In vitro release study showed that the total amount of drug released from acid-labile polymeric fibers was accelerated on account of pH-induced structural and morphological changes of fibrous mats and the degradation of matrix polymers, and the burst release was significant higher for polymers with higher contents of acid-labile segments. During the investigational period, almost no molecular weight reduction and mass loss was detected in neutral buffer solutions, but the degradation was enhanced in acid buffers with a two-stage degradation profile. Surface erosion mechanism was initially detected for fibrous mats with distinct fiber morphologies, and bulk degradation was determined during the following incubation for polymeric films resulting from the morphological changes.