While the song samples from hip hop (Kool G. Rap's "Poison"), the lines "Never trust a big butt and a smile" and "The J, the I, the M, the M, The Y" (originally from Boogie Down Production's 1988 classic "Jimmy") reflected a new era of AIDS consciousness and would quickly become a staple of hip hop. In the outro, BBD gives shout-outs to their former New Edition bandmates, Bobby Brown, Ralph Tresvant and Johnny Gill.
On the Billboard Hot 100 singles chart, "Poison" rose from number fifty-two to number thirty-eight in the week of April 14, 1990, and eventually peaked at number three for four consecutive weeks, beginning on June 9, 1990. The single also peaked at number one on the Hot Black Singles chart for two weeks. "Poison" became one of the most successful singles of 1990 (see 1990 in music), and was a staple on MTV and mainstream radio in the summer, spending ten weeks in the Top 10. The single peaked at number seven on the dance charts. "Poison" was certified platinum by the RIAA on June 1, 1990 for sales of over one million copies.