This study applied latent class analysis to a family-centered prevention trial in early childhood to identify subgroups of families with differential responsiveness to the Family Check-Up (FCU) intervention. The sample included 731 families with 2-year-olds randomized to the FCU or control condition and followed through age 5 with yearly follow-up assessments. A two-step mixture model was used to examine whether specific constellations of family characteristics at age 2 (baseline) were related to intervention response across ages 3, 4, and 5. The first step empirically identified latent classes of families based on several family risk and adjustment variables selected on the basis of previous research. The second step modeled the effect of the FCU on longitudinal change in children’s problem behavior in each of the empirically derived latent classes. Results suggested a five-class solution, where a significant intervention effect of moderate-to-large size was observed in one of the five classes—the class characterized by child neglect, legal problems, and parental mental health issues. Pairwise comparisons revealed that the intervention effect was significantly greater in this class of families than in two other classes that were generally less at risk for the development of child disruptive behavior problems, albeit still low-income. Thus findings suggest (a) the FCU is most successful in reducing child problem behavior in more highly distressed, low-income families, and (b) the FCU may have little impact for relatively low-risk, low-income families. Future directions include the development of brief screening process that can triage low-income families into groups that should be targeted for intervention, redirected to other services, monitored prospectively, or left alone.