OBJECTIVE: Epidural steroid injections (ESIs) are a commonly utilized treatment for lumbosacral radicular pain caused by intervertebral disc herniation or stenosis. Although effective in certain patient populations, ESIs have been associated with serious complications, including paralysis and death. In 2014, the US Food and Drug Administration (FDA) issued a safety warning on the risk of injecting corticosteroids into the epidural space. The aims of this article were to review the neurological complications associated with ESIs and to compare the formulations, safety, and effectiveness of commercially available corticosteroids given by transforaminal, interlaminar, or caudal injection. METHODS: Serious adverse events associated with ESIs were identified by a search of the FDA Adverse Event Reporting System (FAERS) database. A MEDLINE search of the literature was conducted to identify clinical trials comparing the safety and effectiveness of nonparticulate and particulate corticosteroid formulations. RESULTS: Neurological complications with ESIs were rare and more often associated with the use of particulate corticosteroids administered by transforaminal injection. Among the 10 comparative-effectiveness studies reviewed, 7 found nonparticulate steroids had comparable efficacy to particulate steroids, and 3 studies suggested reduced efficacy or shorter duration of effect for nonparticulate steroids. DISCUSSION: The risk of complications for transforaminal ESI is greater with particulate corticosteroids. Nonparticulate corticosteroids, which are often recommended as first-line therapy, may have a short duration of effect, and many commercial formulations contain neurotoxic preservatives. The safety profile of ESIs may continue to improve with the development of safer, sterile formulations that reduce the risk of complications while maintaining efficacy.