Background: Objective of the study was to assess whether second generation antihistaminic alter psychomotor and cognitive function in comparison with promethazine (marked sedation; altered psychomotor and cognitive impairment).Methods: It was a single blind prospective study. Seventy five healthy human volunteers were registered, divided in five groups. These groups have received placebo, promethazine 25 mg, cetirizine 10 mg, fexofenadine 120 mg and loratadine 10 mg. Cognitive and psychomotor functions were assessed pretreatment and 60 minutes after single dose of drug(post treatment)by using a battery of standard tests (e.g. PST-Perceptual speed test, BVRT-Benton visual retention test,SSS- Stanford Sleepiness Scale, FTT-Finger tapping test etc.). The data were analyzed by student’s t-test and ANOVA test.Results: No significant effect was observed in any test parameter with placebo and fexofenadine. Significant difference with promethazine in PST, BVRT, SSS and cetirizine in DSST, FTT and loratadine in DSST were observed. Significant difference was observed in DSST between the placebo and promethazine, in SSS between promethazine and all other drugs. In FTT and BVRT significant difference between the groups were observed.Conclusions: Significant sedation and altered cognitive and psychomotor function were observed with promethazine. Cetirizine and loratadine do not cause sedation but both affect psychomotor functions. No significant effect was produced by fexofenadine. Thus, fexofenadine can safely be used in persons involved in activity where alertness is required while cetirizine and loratadine should be avoided.