According to the USP erythromycin determination in finished oral products as well as in some topical formulations is mainly carried out via microbiological assays. However, these assays are known for their long incubation periods, lack of precision and low sensitivity. In literature one HPLC method for the quantification of erythromycin in creams is described, which depends on electrochemical detection, but HPLC electrochemical detection has not emerged as popular choice in routine analysis. Furthermore two other HPLC-UV methods are described for the isolation of erythromycin from gels and creams involving tedious and time consuming extraction steps, the reason why they are not suited to be applied in routine analysis. This paper describes a new HPLC-UV method for the determination of erythromycin in creams, which implies a much easier extraction procedure than that cited in literature to date, based solely on the solubilization of erythromycin followed by freezing the cream matrix. Validation experiments confirmed the precision and accuracy of the method. Good linearity of the assay was found over the investigated concentration range of 70-130% (corresponding to 0.77-1.43 g of erythromycin A in 100 g cream base). The coefficient of correlation resulting from unweighted linear regression was 0.9998, allowing a one-point calibration in routine analysis. By the implementation of an internal standard in the quantification of erythromycin an improved precision could be achieved in routine analysis. This new analytical method yields cleaner extracts and allows a higher throughput, saving costs, solvents and time and can be thus recommended to all laboratories.