Rickettsia parkeri rickettsiosis is recognized as the second most prevalent tick-borne disease caused by spotted fever group rickettsiae in the Americas, where two pathogenic strains (R. parkeri sensu stricto and R. parkeri strain Atlantic rainforest) have been related to human infections and transmitted by Amblyomma spp. ticks. We developed a systematic review that evaluated all available evidence in the literature regarding clinical, epidemiological, and laboratory features of R. parkeri rickettsiosis, including confirmed and probable cases. We followed the recommendations made by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guide. We excluded papers that contained missing information of some variables and publications in which it was not possible to separate data for confirmed and probable cases. A total of 77 clinical cases (32 confirmed cases and 45 probable cases) were considered for this review. Overall, our results show that R. parkeri rickettsiosis is more frequent in males in the age group of 18-64 years and that a history of tick exposure was frequent (>90%). Cases were described in the United States, Argentina, Brazil, Uruguay and Colombia. Clinically, more than 60% of the cases had fever (mean of 93%), eschar (mean of 87%), and rash (mean of 68%). Headache and myalgia were predominant nonspecific symptoms (mean of 67% and 61%, respectively). Our results show that at least 60% of R. parkeri cases had altered laboratory parameters, most often showing an increase in transaminases and leukopenia. Tetracyclines-class antibiotics were used in most (>85%) of the patients. Overall, only 9% of cases required hospitalization and there was a 100% rate of clinical recovery in all of cases.