Abstract Background Current guidelines suggest specific criteria for oral or long-acting injectable antipsychotic drugs (LAIs). This review aims to describe the demographic and clinical characteristics of the ideal profile of the patient with schizophrenia treated with LAIs, through the analysis of nonrandomized studies. Methods A systematic review of nonrandomized studies in English was performed attempting to analyze the factors related to the choice and use of LAIs in daily practice. The contents were outlined using the Cochrane methods for nonrandomized studies and the variables included demographic as well as clinical characteristics. The available literature did not allow any statistical analysis that could be used to identify the ideal profile of patients with schizophrenia to be treated with LAIs. Results Eighty publications were selected and reviewed. Prevalence of LAI use ranged from 4.8% to 66%. The only demographic characteristics that were consistently assessed through retrieved studies were age (38.5 years in the 1970’s, 35.8 years in the 1980’s, 39.3 years in the 1990’s, to 39.5 years in the 2000’s) and gender (male > female). Efficacy was assessed through the use of various symptom scales and other indirect measurements; safety was assessed through extrapyramidal symptoms and the use of anticholinergic drugs, but these data were inconsistent and impossible to pool. Efficacy and safety results reported in the different studies yielded a good therapeutic profile with a maximum of 74% decrease in hospital admissions and the prevalence of extrapyramidal symptoms with LAIs consistently increased at 6, 12, 18, and 24 months (35.4%, 37.1%, 36.9%, and 41.3%, respectively). Conclusions This analysis of the available literature strongly suggests that further observational studies on patients with schizophrenia treated with LAIs are needed to systematically assess their demographic and clinical characteristics and the relationships between them and patient outcome. Besides the good efficacy and safety profile of LAIs, health care staff must also take into account the importance of establishing a therapeutic alliance with the patient and his/her relatives when selecting the most appropriate treatment. LAIs seem to be a good choice not only because of their good safety and efficacy profile, but also because they improve compliance, a key factor to improving adherence and to establishing a therapeutic alliance between patients with schizophrenia, their relatives, and their health care providers.