A laboratory-scale anaerobic sequencing batch reactor was used to treat a model substrate mixture representing pharmaceutical wastewater at an organic loading rate of 2.9 g COD/(L d). After reaching stable operation the reactor was first exposed to low (1 mg/L) and, subsequently, to high (200 mg/L) concentrations of the antibiotic erythromycin. The addition of low levels of erythromycin resulted in a significant but limited reduction of biogas production by 5% and the higher level of erythromycin did not impact biogas production further, suggesting that a substantial fraction of the microbial populations in the ASBR were resistant to the antibiotic. Effluent soluble COD could not be accounted for in measured volatile fatty acids, perhaps suggesting the production of soluble microbial products. In batch tests evaluating the specific methanogenic activity, conversion of the model substrate mixture was only slightly affected by the presence of erythromycin. However, the conversion of butyric acid was inhibited when erythromycin was present. After 47 days of exposure to erythromycin, the conversion of butyric acid was inhibited to a lesser extent, suggesting the development of antibiotic resistance in the biomass. Exposure to antibiotics can affect specific substrate degradation pathways, leading to the accumulation of volatile fatty acids, soluble microbial products, and potentially to overall system instabilities.