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Substance may refer to:
- Chemical substance, a material with a definite chemical composition
- Drug substance
- Substance abuse, drug-related healthcare and social policy diagnosis or label
- Substance dependence, drug-related healthcare and social policy diagnosis or label
- Matter, anything that has mass and takes up space
- Substance theory, theory positing that a substance is distinct from its properties
- Substance (Joy Division album), 1988
- Substance (Blank & Jones album), 2002
- Substance 1987, a New Order album
- "Substance", a song by Haste the Day from That They May Know You
- Metal Gear Solid 2: Substance, an update of the video game Metal Gear Solid 2: Sons of Liberty
- Homoousian, a Christian term meaning "same substance"
- Stanley Robinson, known as Substantial, an international hip-hop artist.