Abstract Background The vital signs reflect the physiological state of patients in various clinical conditions. The purpose of this study was to compare the effects of cold compress and Xyla-P cream on hemodynamical changes during venipuncture in hemodialysis patients. Methods and Material In this clinical trial study, 50 patients under hemodialysis were selected by simple random sampling. The patients were then randomly assigned to either Xyla-P cream, cold compress or placebo groups. The vital signs (blood pressure and pulse) were measured upon two intermittent hemodialysis sessions before and after venipuncture. Data were analyzed using repeated measures analysis of variance. Results The mean alternation in systolic blood pressure was significantly different comparing the placebo and cold compress groups before and after intervention (p<0.001). However, the difference was not significant between the Xyla-P cream group and either placebo (p=0.402) or ice compress (p=0.698) groups. The difference of the mean diastolic blood pressure was significant comparing the placebo group with either the Xyla-P cream group (p=0.003) or cold compress group (p<0.001) before and after intervention. In addition, there was a significant difference in the mean number of heartbeats comparing the control group with either the Xyla-P cream group (p<0.001) or cold compress group (p<0.001) before and after the intervention. Conclusions Considering the beneficial effects of ice compress and the Xyla-P cream on reduction of cardiovascular parameters, it is recommended to use these methods in hemodialysis patients during venipuncture.