Objective To examine the correlations of Paliperidone plasma concentration with drug dose, clinical efficacy and side effects in patients with schizophrenia. Methods The patients with schizophrenia were treated by Paliperidone. The plasma concentration was monitored by high-performance liquid chromatography-tandem mass spectrometry (RP-HPLC) at the end of the 1st, 2nd and 4th week. The clinical efficacy was evaluated using the Positive and Negative Syndrome Scale (PANSS) and the side effects were evaluated by the Treatment Emergent Symptom Scale (TESS) at the baseline and at the end of the 1st, 2nd and 4th week after treatment. The blood routine, urinalysis, liver and kidney functions, electrocardiogram and prolactin level detection were done at baseline and the 4th weekend after treatment. Results The Paliperidone dosages [(7.24 ±1.50), (8.89 ± 1.29), (9.63 ± 1.77)] were positively correlated with the blood concentrations [(18.64 ± 7.93), (25.44 ± 10.71), (27.65 ±13.89)] at the end of the 1st, 2nd and 4th week after treatment (P < 0.05). The plasma concentration of Paliperidone was correlated with serum prolactin level in the female patients (P < 0.05). The plasma concentration of Paliperidone was not correlated with the reduction rate of PANSS scores, TESS or the value of weight gain (P > 0.05). There was no significant difference in the plasma concentration of Paliperidone between the effective and ineffective groups or between the extrapyramidal reaction group and the non-extrapyramidal reaction group (P > 0.05). Conclusions There is a positively nonlinear correlation between the plasma concentration and the dose of Paliperidone. There is a positive correlation between the Paliperidone plasma concentration and serum prolactin level.