ORD and CD spectra are reported for a series of penicillin antibiotics and related degradation products. The results, when compared with published X-ray data, suggest that some conformational changes can apparently go undetected by chiroptical techniques in this series and that the side chain substituent at C₆ plays a relatively minor role in determining the sign and intensity of the COTTON effect unless its stereochemistry is inverted. The rather large spectroscopic effect following C₆-epimerization has potential for development as an assay for the percentage of 6-epihetacillin in a given mixture. Some preliminary data are presented showing the utility of this method for investigating the kinetics of C₆-epimerization. Semiempirical predictive rules developed for simple amides are inadequate for rationalizing the penicillin spectra. The origin of the COTTON effects is briefly discussed and contrasted with the cephalosporin antibiotics.