Attending day care is associated with recurrent respiratory infections (RRIs) and asthma. Ribosomal immunotherapy may confer protection against RRIs in children. This study was designed to assess the efficacy of a ribosome-component immune modulator (RCIM) as preventive treatment of respiratory infections in socialized children aged ≤5 years, with or without a history of frequent RRI. In a multicenter, Italian, randomized, double-blind, placebo-controlled, parallel-group study, 164 socialized day care center children (mean age, 3.8 ± 1.1 years) were treated with RCIM or placebo for 6 months and followed-up for additional 6 months. Outcomes are presented for the intent-to-treat population. In socialized children with five or less RRIs (n = 95; 49 RCIM and 46 placebo, group A) the duration of the infectious episodes was significantly shorter with RCIM than with placebo (6 months, 3.7 ± 2.1 versus 4.5 ± 1.9 days, p = 0.040; 12 months, 3.6 ± 2.0 versus 4.7 ± 2.5 days, p = 0.015). The proportion of patients reporting no respiratory infectious episodes with RCIM at 6 and 12 months was also significantly larger in group A (20.4% versus 4.4% placebo; p = 0.028). No such differences were found in children with more than five RRIs in the preceding year (n = 63; 32 RCIM and 31 placebo, group B). In all children, general well-being improved significantly more under RCIM than under placebo (11.6 ± 1.8% versus 10.2 ± 1.8%; p = 0.002). No statistically significant between-treatment differences were observed for other end points. Both treatments were similarly well tolerated. Six-month treatment with RCIM effectively prevented the 12-month risk of RRIs in children <5 years old and with five or less RRIs in the preceding year.