The benzamide compound metoclopramide (MCP) protects against cholinesterase inhibition by paraoxon (POX) both in vitro and in vivo. This study evaluates MCP-conferred protection of enzyme activity head to head against the therapeutic gold standard pralidoxime (PRX). Six groups of rats were used. All substances were applied i.p. daily for 5 days, followed by a 2-day rest. The 7-day cycle was repeated eight times. Group 1 received 100 nM POX, group 2 received 50 µM MCP, group 3 received 100 nM POX + 50 µM MCP, group 4 received 50 µM PRX, group 5 received 100 nM POX + 50 µM PRX and group 6 received saline. Red blood cell acetylcholinesterase (RBC-AChE) measurements were performed at baseline and on day 5 of each 7-day cycle. The sums of enzyme activities over time (weekly values expressed as % of baseline of 100%) were compared using the Mann–Whitney rank order test. A Bonferroni correction of 4 for multiple comparisons was applied. Paraoxon signiﬁcantly reduced enzyme activities when compared with saline (Σ = 535 ± 25 vs 902 ± 42). Metoclopramide conferred statistically signiﬁcant in vivo protection from inhibition of RBC-AChE by POX (Σ = 640 ± 58). The extent of protection was signiﬁcantly less than that conferred by the gold standard PRX (Σ = 765 ± 57). Metoclopramide, in addition to being less effective as an RBC-AChE protective agent, also caused a failure to thrive in the POX+MCP-exposed rats, as evidenced by the changes in body weight. Copyright © 2004 John Wiley & Sons, Ltd.