Upper respiratory tract infections (URTIs) are highly prevalent and impose substantial individual and societal burdens. Plasmacytoid dendritic cells (pDCs) are major producers of type I interferons (IFNs) with antiviral activity. This study investigated whether CpG oligodeoxynucleotide-induced IFN-α production by peripheral blood mononuclear cells (PBMCs), a marker of pDC activity, was associated with subsequent occurrence of the common cold. Data from 41 healthy adults in the placebo arm of a randomized controlled trial were analyzed. CpG-induced IFN-α production was measured before a 4-week observation period, and participants were dichotomized into high and low IFN-α production groups based on the median value. The occurrence of common cold events and cold symptoms was assessed using daily self-reported symptom scores and body temperature records. Seven participants developed the common cold, all in the low group. The crude risk difference between the low and high groups was 0.333 (Miettinen–Nurminen 95% CI, 0.148–0.546; Fisher’s exact p = 0.009). The low group also showed higher risks for fever, plugged nose, and sore throat, while findings for the other symptoms were less conclusive. As a hypothesis-generating pilot study, these findings suggest that low TLR9-mediated IFN-α production may be associated with increased susceptibility to URTIs in healthy adults.