Diagnosis of an autism spectrum disorder (ASD) requires a qualitative assessment of social aptitude: one person judging whether another person interacts in a “typical” way. We hypothesized that mice could be used to make a similar judgment if they prefer “typical” over “atypical” social interactions with mouse models relevant to ASD. We used wild-type C57BL/6 (B6) mice as “judges” and evaluated their preference for a chamber containing a “typical” (B6 or 129S6) or an “atypical” mouse. For our atypical mouse stimuli, we chose two inbred strains with well-documented social phenotypes (BTBR and BALB/c), as well a mutant line with abnormal social behavior and seizures (Gabrb3 +/−). Overall, we observed a stimulus by time interaction (P < 0.0001), with B6 mice preferring the typical mouse chamber during the last 10 min of the 30-min test. For two of the individual stimulus pairings, we observed a similar chamber by time interaction (BALB/c vs. 129S6, P = 0.0007; Gabrb3 +/− vs. 129S6, P = 0.033). For the third stimulus pairing, we found a trend for preference of the typical mouse across time (BTBR vs. B6, P = 0.051). We repeated the experiments using 129S6 mice as judges and found a significant overall interaction (P = 0.034), but only one stimulus pairing reached significance on its own (BALB/c vs. 129S6, P = 0.0021). These data suggest that a characteristic pattern of exploration in B6 mice can distinguish some socially atypical animals from controls. Autism Res 2013, 6: 212–220. © 2013 International Society for Autism Research, Wiley Periodicals, Inc.