Fibroblast-like cells derived from guinea-pig skin were cultured for 3 h in the presence of various concentrations of histamine. The total protein synthesized was determined by the incorporation of radioactive proline, and the collagenous protein synthesized was measured by the incorporation of labeled hydroxyproline in the cell layer and medium. Synthesis of both total and collagenous protein increased in the presence of histamine in the concentration range of 10(1)-10(3) micrograms/ml. The ratio of collagen to total protein synthesized also increased at these concentrations. However, in no case was an increase found when H1 antagonist (chlorpheniramine) and H2 antagonist (cimetidine) were added with the histamine. DNA synthesis was not affected by histamine at the concentrations used. These results suggest that histamine increases the synthesis of collagen by fibroblast-like cells through H1 and H2-receptors.