Spinal manipulation (SM) is a popular form of treatment of back and neck pain, as well as of other conditions. Uncertainty exists as to its safety. The aim of this systematic review was to summarize the data of all prospective investigations into the safety of SM. Five independent literature searches were carried out to identify all such studies. Data were extracted and validated according to pre-defined criteria. Five investigations met the inclusion criteria. The most valid studies suggest that about half of all patients will experience adverse events after chiropractic SM. These events are usually mild and transient. No reliable data exist about the incidence of serious adverse events. These data indicate that mild and transient adverse events seem to be frequent. Serious adverse events are probably rare but their incidence can only be estimated at present. Further prospective investigations are needed to define their incidence more closely.