I was analyzing plasma samples using LC-MS/MS for a drug quantification study. The standard curve looked great in pure solvent, but when I injected extracted plasma samples, the signal dropped significantly.

After some digging, I realized the problem was ion suppression caused by co-eluting matrix components. These were interfering with ionization efficiency in the ESI source.

Switching to solid-phase extraction (SPE) instead of protein precipitation helped clean up the matrix, and the response came back to normal. Ever since, I always test for matrix effects early in method development.