Abstract In guinea pigs immunized with human acid-soluble type I collagen in the native form immunological cross-reactivity with the collagen-like fragment of human Clq, CLF,§ was observed. At the cellular level, this fragment elicited a clear-cut delayed-type hypersensitivity reaction in 11 out of 20 collagen-immunized guinea pigs as demonstrated in skin tests after injection of 10–100 μg CLF. These 11 animals, and only these, also showed positive skin reactions when challenged with low doses of native collagen (2.0 μg). At the humoral level, only one animal had anticollagen antibodies that cross-reacted with CLF both in passive hemagglutination and solid-phase radioimmunoassay. Depending on the detection method used, only five (seven) animals showing cell-mediated cross-reactivity with CLF were also found to be anticollagen-antibody-positive.