Abstract Two small cell lung cancer (SCLC) cell lines were established from metastases of a patient during the course of the disease. SCLC 74A was derived from biopsy material obtained at the time of diagnosis and SCLC 74 B was from a biopsy specimen of a relapsed tumor obtained after treatment. A transition occurred from SCLC 74 A, an intermediate form with 5% large cells to SCLC 74 B, a standard mixed form with 20% of large cells, with a decrease in neuroendocrine markers and a substantial increase in P-glycoprotein, a multidrug resistance marker. For both cell lines, R-banding and FISH indicated a del(1)(p35pter) also found in other neural-crest-derived tumors, the loss of regions with suspected tumor suppressor genes at 3p, 5q, and 17p, and a recurrent translocation of the 6q24-6qter region to 10p14. Further genetic modifications in SCLC 74 B affected chromosomes 2, 3, 5, 10, 11, 14, and 15. The main observations were a der(2)t(2;5)(p16;q?); a der(3;11)(q10;p10) in SCLC 74 A which became der(3;14)(q10;p10) and der(11;14)(p10;q10) in SCLC 74 B; and the insertion of the 5q13–5q31 region in the der(10)t(6;10). The finding of the same structural abnormalities in both cell lines suggests a monoclonal origin for both metastases. Hypotetraploid cells were in the same proportion as large cells whose number was a characteristic feature of each cell line. They possessed twice the same chromosomal alterations observed in the hypodiploid cells. This suggests a permanent process of tetraploidization.