: This study examined the effect of thiotriazinone impurity on the generation of insoluble microparticles IMPs associated with ceftriaxone-calcium salt precipitation in original Rocephin and Japanese generic ceftriaxone A ; Sawai, B ; Nichi-Iko products when mixed with Ca 2 4.3 mEq/l. We found that the generation rate of IMPs associated with ceftriaxone-calcium salt precipitation among the three ceftriaxone products tested was in the order of generic A original generic B , as assessed by light obscuration particle counting. Typically, after 60 min, one of the generic ceftriaxone B -calcium mixtures was highly opaque with numerous aggregates of milky-white precipitates, the original ceftriaxone-calcium mixture exhibited noticeable IMPs, and the second generic ceftriaxone A -calcium mixture was transparent. The levels of thiotriazinone contaminants, known to be a major impurity in ceftriaxone products, were determined by HPLC and found to be in the order of generic A original generic B. Moreover, the addition of a small amount of thiotriazinone into the generic ceftriaxone B -calcium mixture significantly decreased the amount of IMPs, suggesting that the impurity retards ceftriaxone-calcium crystal growth. We thus concluded that the thiotriazinone impurity acts as a suppressive factor of ceftriaxone-calcium salt precipitation, and that the high level of thiotriazinone impurity in the ceftriaxone B product could underlie its lowest rate of IMP generation when mixed with calcium. We thus recommend caution regarding the clinical risk of ceftriaxone-calcium compatibility due to impurity contamination in ceftriaxone products.