To determine the optimal route of growth hormone administration, a comparison was made of the acute somatomedin response and chronic growth response to either intramuscular or subcutaneous growth hormone in 20 children with growth hormone deficiency. None of the children had received growth hormone for at least 2 weeks prior to their random selection to receive growth hormone by either the subcutaneous (N = 11) or intramuscular (N = 9) route. Plasma samples for determination of levels of insulin-like growth factors I and II (IGF-I and IGF-II) were obtained prior to therapy and 20 hours after the first and fourth of four daily injections of growth hormone. Growth rate and growth hormone antibody levels were determined before and after 6 months of therapy. IGF-I levels tripled in both treatment groups after four days of growth hormone injections, whereas IGF-II levels nearly doubled, with no significant difference between the intramuscular or subcutaneous group. After 6 months of therapy, there was no significant difference in growth rate and only two patients had developed growth hormone antibodies. Both patients and parents expressed a preference for the subcutaneous method. The identical rises in the IGF-I and IGF-II levels following a brief course of either subcutaneous or intramuscular injections of growth hormone, the similar growth rates, the low incidence of antibody development, and the preference for the subcutaneous route all suggest that the subcutaneous route is the method of choice for chronic growth hormone therapy.