This longitudinal study of 194 very low birth weight (VLBW) and 184 normal birth weight (NBW) infants, hypothesized that the causal pathway between birth group (VLBW, NBW) and mutans streptococci (MS) acquisition (presence) at 18-20 months is mediated by biological, behavioral, and caregiver MS levels. Biological (number of teeth at 8 and 18-20 months, enamel hypoplasia) and behavioral (brushing/cleaning, sweet snacks, breast feeding, dental access) factors were assessed using dental exams and caregiver questionnaire responses at 8 and 18-20 months. Infant MS acquisition and caregiver levels were assessed from saliva and plaque samples collected at 8 and 18-20 months. Structural equations model evaluated the causal pathway with latent variables for biology and behavior. MS presence was similar between birth groups at 18-20 months (VLBW: 40%; NBW: 49%), but significantly higher for NBW at 8 months. Increased number of teeth at 8 and 18-20 months was associated with biological risk. Infants whose caregivers had a one point higher score on MS had a significantly 1.5 higher odds of MS presence. Caregiver behavior was not associated with MS presence. Early Intervention efforts should focus on delaying initial acquisition and improving caregiver awareness of taking care of erupting primary teeth.