The present work is based on a study of the effect of some vitamins such as riboflavin (RF), nicotinamide (NA) and alpha-tocopherol (TP) on the photodegradation of ascorbic acid (vitamin C) (AH2) in oil-in-water cream formulations using a UV irradiation source. A UV spectrophotometric and the official iodimetric methods have been used for the assay of AH2 in cream formulations. These methods have been validated in the presence of RF, NA and TP before their application to the creams. The recoveries of AH2 in the creams are in the range of 90–95% and the reproducibility of the method is within ±5%. The apparent first-order rate constants (kobs) for the photodegradation of AH2 in the presence of RF, NA and TP, individually, in the creams have been obtained. The second-order rate constants for the photochemical interaction of AH2 and the vitamins RF, NA and TP have been determined from the plots of kobs for AH2 photolysis versus the individual vitamin concentration along with the values of k0 from the intercept on the vertical axis. The values of k0 in the presence of RF and NA are lower than those of the kobs, indicating that these vitamins act as photosensitizers for the degradation of AH2 in creams. On the contrary, the value of k0 in the presence of TP is higher than that of the kobs, suggesting a stabilizing effect of this vitamin on the degradation of AH2 in creams. The mode of interaction of the individual vitamins with AH2 on photolysis has been discussed.