Seventy-eight newborn infants born to mothers with serologic evidence of syphilis (positive serum rapid plasma reagin and fluorescent treponemal antibody-absorption tests) were prospectively evaluated to derive diagnostic and therapeutic criteria for congenital syphilis. Sixty-one infants were asymptomatic with normal serum IgM and normal roentgenograms (Group I). Eight infants had clinical and/or laboratory evidence of infection at birth (Group II). Nine infants presented with late onset infection (Group III). Elevated serum IgM and abnormal roentgenologic findings were consistently present in symptomatic infants in Groups II and III. Cerebrospinal fluid (CSF) examination was normal in all asymptomatic infants and in all infants with late onset disease. One of the eight infants in Group II examined at birth had positive CSF Venereal Disease Research Laboratory determinations, but all other CSF findings were within normal limits, and a second infant with a slight increase in CSF protein had no clinical evidence of central nervous system (CNS) involvement. Of those asymptomatic infants who returned for follow-up 75% and 100% were seronegative by 3 and 6 months, respectively. The symptomatic infants remained seropositive up to 18 months of age. Infants who had no clinical evidence of CNS involvement at birth remained normal at follow-up and had normal CSF findings. The two infants with CNS symptoms at birth continued to have developmental delay despite normal CSF findings. The incidence of CNS involvement in congenital syphilis appears to be extremely low. The value of routine spinal fluid examination is discussed.