Purpose Particulate steroids used in epidural steroid injections have been suspected as a cause of post-procedural embolic events. Some particulate steroids have been suspended only when the transforaminal approach is used for an epidural block of the spine. In contrast, non-particulate steroids are generally accepted for safety during epidural steroid injections. However, the safety of using a mixture of non-particulate steroids and local anesthetics is unknown. This study analyzed whether mixtures of commonly used non-particulate steroids and local anesthetics form crystals in solution. Methods We mixed non-particulate steroids (betamethasone sodium phosphate, dexamethasone sodium phosphate, and dexamethasone palmitate) and local anesthetics (ropivacaine, levobupivacaine, bupivacaine, and lidocaine) at different ratios. We used fluorescence microscopy to observe whether crystals formed in mixed solutions; we also measured the pH of each steroid, local anesthetic, and the mixtures. Results Ropivacaine or levobupivacaine and betamethasone sodium phosphate produced large crystals (>50 µm). Ropivacaine or levobupivacaine and dexamethasone sodium phosphate produced small crystals (<10 µm). Lidocaine and all non-particulate steroids produced no identifiable crystals; dexamethasone palmitate and all local anesthetics did not form significant particulates. Betamethasone sodium phosphate and dexamethasone sodium phosphate demonstrated basic pH, while all local anesthetics demonstrated acidic pH. Mixtures showed a wide pH range. Conclusion Non-particulate steroids can form crystals upon combination with local anesthetics. Crystal formation may be caused by alkalinization of steroids. The mixing of ropivacaine or levobupivacaine and betamethasone sodium phosphate may require caution during an epidural steroid injection. Lidocaine or bupivacaine is recommended as a local anesthetic. Dexamethasone palmitate is a candidate for a mixture, but additional studies on its safety and effectiveness are needed.