Pigs are extensively used for biomedical research as animal models given their similarities to humans including size, arterial capacity, and cutaneous structure. While their size also allows for the use of clinically available anesthesia equipment (for example, endotracheal tubes and ventilators), anecdotes exist with respect to stress reactions after exposure to volatile anesthetics. Over 3 mo at our institution, 11 pigs (Sus scrofa domesticus) exposed to isoflurane anesthesia during 2 research protocols were euthanized after exhibiting clinical signs of malignant hyperthermia, including hyperthermia, hypercapnia, skeletal muscle rigidity, dyspnea, tachycardia, and hypotension. This group was composed of intact Yorkshire/Landrace crosses (68 to 91 kg) purchased from a research breeder. While malignant hyperthermia is caused by a mutation in ryanodine receptor 1 (RYR1), another unnamed porcine stress syndrome is caused by a dystrophin defect. We analyzed the incidence of the RYR1 mutation and a dystrophin variant in 9 of the originally clinically affected pigs and in 56 subsequent pigs. All animals tested negative for the RYR1 mutation, while the dystrophin variant was found in 2 out of 7 clinical (28.6%) and 22 out of 46 (47.8%) subsequently tested female pigs. Creatine kinase, indicative of muscle damage, was slightly elevated at baseline in dystrophin variant-positive carriers, albeit not significantly. However, for the original clinically affected pigs, the increase in body temperature while under anesthesia was significantly greater in dystrophin variant-positive carriers (7.9 ± 0.8 °C) compared with noncarriers (5.2 ± 0.6 °C, P = 0.046). Taken together, we describe the suspected involvement of a dystrophin variant as one of the genetic etiologies in an unnamed condition that has been anecdotally experienced by pig researchers but not reported. We propose naming this condition volatile anesthesia porcine stress syndrome (VAPSS), which is an umbrella term that includes multiple genetic origins, the most well-known of which is malignant hyperthermia stress syndrome in pigs. Identifying other etiologies for VAPSS has implications for genetic and clinical screening to improve welfare in pigs bred for biomedical research and agricultural purposes.