Phenylephrine and pseudoephedrine are both decongestants and can both be found in numerous over-the-counter formulations marketed as treatments for cold and allergy symptoms. They are significantly different, however, in many respects. Pseudoephedrine is derived from a naturally occurring substance, ephedra, which is found in many plant species. It is also a stimulant of the amphetamine class. Phenylephrine is a synthetic chemical used to increase blood pressure and as a detumescent.

On a molecular level, phenylephrine and pseudoephedrine differ significantly. Pseudoephedrine has a chemical formula of C₁₀H₁₅NO. Phenylephrine has a chemical formula of C₉H₁₃NO₂. Unlike pseudoephedrine, phenylephrine is quickly metabolized by a common gastrointestinal enzyme. This means that the bioavailability, or the amount of a substance taken into the body that is actually absorbed and has an effect, is only 38% for phenylephrine, compared to 100% for pseudoephedrine.

Phenylephrine and pseudoephedrine, while both used as nasal decongestants, are in different chemical classes. Pseudoephedrine, as an amphetamine, is a stimulant that acts to release adrenaline and is easily converted to methamphetamine, a potentially dangerous stimulant that is often used illicitly. Phenylephrine does not have this effect and cannot be used to manufacture methamphetamine. It is often used as an alternative to pseudoephedrine for this reason. It does boost blood pressure, however, but without the stimulant effects of the other drug.

The drugs are also used differently. Pseudoephedrine, in addition to its use as a nasal and sinus decongestant, may also be used for reducing congestion of the eustachian tubes and for helping to suppress coughs. It is also used as a stimulant and as an ingredient in many weight-loss pills.

In addition to acting as a nasal decongestant, phenylephrine can be used to boost blood pressure without increasing heart rate. This gives it an advantage over pseudoephedrine in this respect as pseudoephedrine will increase heart rate, sometimes dramatically. Phenylephrine is also sometimes used to dilate pupils, which makes it useful for some types of eye examinations. It is sometimes used to treat priapism as well.

The side effects of phenylephrine and pseudoephedrine also differ from one another. Phenylephrine has fewer possible side effects and is much less likely to cause hypertension, anxiety, sleeplessness, or heart palpitations. Pseudoephedrine is not recommended for people with several health conditions including diabetes, certain types of glaucoma, heart conditions, and pregnancy. Pseudoephedrine's possible use in manufacture of methamphetamine has also resulted in its sale and use being regulated by law in many countries. It is also listed as a banned substance by many sports organizations.