Attenuation of organic compounds in sewage treatment plants (STPs) is affected by a complex interplay between chemical (e.g. ionization, hydrolysis), physical (e.g. sorption, volatilization), and biological (e.g. biodegradation, microbial acclimation) processes. These effects should be accounted for individually, in order to develop predictive cheminformatics tools for STPs. Using measured data from 70 STPs in the Netherlands for 69 chemicals (pharmaceuticals, herbicides, etc.), we highlighted the influences of 1) chemical ionization, 2) sorption to sludge, and 3) acclimation of the microbial consortia on the primary removal of chemicals. We used semi-empirical corrections for each of these influences to deduce biodegradation rate constants upon which quantitative structure-biodegradation relationships (QSBRs) were developed. As shown by a global QSBR, biodegradation in STPs generally relates to structural complexity, size, energetics, and charge distribution. Statistics of the global QSBR were reasonable, being R2training = 0.69 (training set of 51 compounds) and R2validation = 0.50 (validation set of 18 compounds). Class-specific QSBRs utilized electronic properties potentially relating to rate-limiting enzymatic steps. For class-specific QSBRs, values of R2 of in between 0.7 and 0.8 were obtained. With caution, environmental risk assessment methodologies may apply these models to estimate biodegradation rates for ‘data-poor’ compounds. The approach also highlights ‘meta data’ on STP operational parameters needed to develop QSBRs of better predictability in the future.