The aim of the present study was to explore whether mice fed a diet low in Zn (2.0 mg Zn/kg diet) for a relatively short period of time were more prone to severe Streptococcus pneumoniae infection than mice fed a normal diet (25 mg elemental Zn/kg). The Zn-deficient mice were compared with mice in two Zn-adequate control groups; one pair-fed and another with free access to the diet. After 2 weeks feeding, the mice were infected intranasally under anaesthesia with a suspension containing about 107 pneumococci. Clinical status was observed every day and blood samples were examined for S. pneumoniae every second day for a week. All infected mice examined carried the infecting strain intranasally. The survival time and time before positive blood culture were significantly shorter in the Zn-depleted group than in the pair-fed Zn-adequate group (hazard ratios 15.6 and 3.2, P < 0.0001 and P = 0.045 respectively). At the end of the observation period, ten of the twelve mice in the Zn-deficient group were dead while one of twelve and two of twelve were dead in the two Zn-adequate control groups. This study shows that even acutely-induced Zn deficiency dramatically increases the risk of serious pneumococcal infection in mice.