Bed bugs (Cimex spp.) have undergone a global resurgence over the last 15–20 years. They readily bite humans, producing a range of cutaneous reactions. This article documents systemic reactions in two patients following repeated bites from the common bed bug, Cimex lectularius. Both patients had previously fed bed bugs on themselves without any serious complication, however upon feeding a new batch of the insects subsequently developed systemic urticarial reactions. Patient 1 fed 40–50 bed bugs on himself and after 8 min, he developed itch, swelling of the face, lethargy, profuse sweating and widespread wheals on the torso and limbs. The reaction disappeared in 5 h after treatment with systemic prednisone and antihistamines. Patient 2 developed a similar reaction after feeding five to six bed bugs on himself. In this case, the patient also developed chest tightness and breathing difficulties. Following a similar treatment, symptoms disappeared in 4 h. In light of the increasing exposure of this insect to the general public, systemic reactions in patients may present more commonly to the medical practitioner.