BACKGROUND: Interscalene brachial plexus block (ISB) may be followed by cardiovascular instability. Until date, there is no clear picture available about the underlying mechanisms of ISB. In this study, we aimed to determine the changes in heart rate variability (HRV) parameters after ISB and the differences between right- and left-sided ISBs. METHODS: We prospectively studied 24 patients operated for shoulder surgery in sitting position and divided them into two respective groups: R (right-sided block = 14 pts) and L (left-sided block = 10 pts). HRV data were taken before and 30 min after the block. Ropivacaine without ephedrine was used for the ISB through an insulated block needle connected to a nerve stimulator. Statistical analysis implemented chi-square, Student's and t-paired tests. Skewed distributions were analyzed after logarithmic transformation. RESULTS: All the studied patients had successful blocks. Horner's syndrome signs were observed in 33.3% of the patients (R = 5/14, L = 3/10; [P = 0.769]). There were no significant differences in pre-block HRV between the groups. The application of ISB had differential effect on HRV variables: R-blocks increased QRS and QTc durations and InPNN50, while a statistical decrease was seen in InLF. L-blocks did not show any significant changes. These changes indicate a reduced sympathetic and an increased parasympathetic influence on the heart's autonomic flow after R-block. CONCLUSIONS: Based on the obtained results we conclude that ISB, possibly through extension of block to the ipsilateral stellate ganglion, alters the autonomic outflow to the central circulatory system in a way depending on the block's side.