There is a great interest in characterizing the biological properties of natural compounds obtained from plants, especially polyphenols. We studied the structure-activity-cytotoxicity relationships of polyphenolic fractions obtained from grape pomace and pine bark. These fractions contained similar polymerised flavonoids but different percentages of pyrogallol groups that confer on them different biological properties. The human keratinocyte cell line HaCaT and the mouse fibroblast cell line 3T3 were used to study the cytotoxicity of the different fractions after 24, 48, and 72 h of exposure. Antioxidant activity of the fractions was evaluated by measuring the inhibition of hemolysis mediated by AAPH. Our results demonstrate that the polyphenolic fractions studied show high antioxidant capacity in a concentration range that is not harmful to normal human cells. Pine fractions presented slightly lower antioxidant activity than grape fractions but are less cytotoxic. This data provides useful information to help design safe antioxidant products that act without altering critical cell functions.