The separation of genetic and environmental trends in a repeat mating design and the effectiveness of such a design in producing genetic response to selection were observed during eight cycles of directional selection for high 12-day litter weight in mice. A random-bred control was used to monitor the repeat mating design in estimating environmental trend. Two mass selection populations (M1 and M2) under different selection intensities were used to assess the success of the repeat mating design in achieving selection response. From the third to the eighth cycle, the estimated genetic gain in 12-day litter weight for the repeat mating population was 0.89 ± 0.25 g per cycle. The selection response from the repeat design was lower than from one mass selection population (M2) but higher than from the other (M1). The environmental trend estimate of −0.79 ± 0.78 g per cycle was in fair agreement with the estimate of −0.88 ± 0.55 g per cycle from the random bred control.