Bone marrow transplants from normal Albany strain guinea pigs established a functional classical pathway of complement (C) in C4-deficient (C4D) guinea pigs. Seventeen days after transplant the Albany leads to C4D chimeras had detectable C4 and total hemolytic C activities. Maximum C4 levels (2 to 8% of normal were reachered by day 73 and restored total C to 40% of normal. Classical pathway function persisted for about 150 days and, thereafter, declined to undetectable levels by day 385. In contrast, Albany guinea pigs transplanted with C4D marrow maintained normal C4 levels throughout the experiment, suggesting that the C4-producing cells are radioresistant and long-lived. Unlike unmanipulated C4D animals, Albany leads to C4D chimeras were unable to produce antibodies to guinea pig C4 when immunized with normal guinea pig serum. These experiments suggest that bone marrow cell progeny produce C4 in vivo.