Objective To compare the compliance， efficacy and safety of three different half-lives of paliperidone in the treatment of schizophrenia. Methods A total of 187 schizophrenic patients who were hospitalized or outpatient treated in the Department of Psychology in the First Hospital of Heber Medical University and Department of Psychiatry in Handan Central Hospital from August 2019 to August 2020 were selected as the study subjects by convenience sampling method. All the patients were assigned to paliperidone sustained-release tablets （Pali-ER， n=65）， one-month paliperidone palmitate （PP1M， n=67）， and 3-month paliperidone palmitate （PP3M， n=55） according to wills of patients and physician， and underwent a 12 months' treatment. Patients were assessed with the Positive and Negative Symptom Scale （PANSS） at baseline， 3， 6， 9， and 12 months， and adverse events and duration of treatment. Results During the study， a total of 27 patients in the Pali-ER group withdrew from the study， of which 21 stopped treatment， 4 changed medication， and 2 were hospitalized； 17 patients in the PP1M group withdrew from the study， of which 9 stopped treatment， 4 changed medication， and 4 were hospitalized； 6 patients in the PP3M group withdrew from the study， of which 5 stopped treatment and 1 changed medication. The mean duration of treatment in Pali-ER group was （9.169±0.506） months （95%CI=8.178-10.161）， which was shorter than that of PP1M group ［（10.254±0.425） months， 95%CI=9.421-11.087］ and PP3M group［（11.455±0.219） months， 95%CI=11.024- 11.885］， and the differences among the 3 groups were statistically significant （P ＜ 0.05）. There was no significant difference in PANSS scores among the three groups at different time periods （P＞ 0.05）. There were statistically significant differences in the occurrence of extrapyramidal reactions and adverse reactions among three groups of patients （P ＜ 0.05）. Conclusions Paliperidone with different half-life has the same efficacy. Patients treated with paliperidone with longer half-life have better compliance and higher safety