The genetic control of strong stimulation in the mixed lymphocyte culture reaction is determined by a separate gene (MLR-S) Recent findings show that the genetic control of stimulation in the mixed lymphocyte culture (MLC) reaction in man is determined by a separate gene (MLR-S) closely linked to the FOUR-locus of the HL-A chromosomal region (1). This gene must be located outside the 1IL-A chromosomal region as indicated by studies of the AILC-reactions within families with recombinations of the major histocompatibility region (MlHlR) between the FOUR-locus and the MILR-S locus (1-8).In this study we present data on three recombinant children with recombination between the FOUR-locus and the MLR-S locus in two families. The MLC data from these families confirms the hypothesis that the MLR-S locus is located outside the HL-A chromosomal region. An analysis of normal material of zero, one, and two iHL-A haplotype different combinations has made it possible to evaluate the MLC results obtained in the HL-A haploidentical, MLR-S identical combinations. This has clarified that more than one gene is responsible for the stimulation in the MLC test. It is concluded, that the MLR-S locus is responsible for a strong allogenie cell stimulation, while one or more genes located within the ilL-A chromosomal region may contribute with a weak Abbreviations: MILC, mixed lymphocyte culture; S1R, stimulation rates; AMiR, major histocompatibility region; SCII), severe (Table 1 and Fig. 1). A total of 479 of these tests represented unrelated IIL-A nonidentical, two-haplotype different combinations, 127 were haploidentical siblings or parent-child combinations, while the remaining 52 tests were performed between HL-A identical siblings. Calculations of the data obtained withiii each of the three groups were based on logratios. The log-value for mean, SD, SE of mean, was determined and the log-ratios were retransformed into simple ratios for further analysis. One family (Minnesota family BR) (