Higher sibling exposure is associated with a reduced risk of asthma and other T helper 2 (Th2)-type disorders, possibly through a beneficial effect of higher infection load. The effect on Th1 disorders such as multiple sclerosis (MS) is less clear. Here we examine the association between asthma and MS, taking into account early life sibling exposure. A population-based case-control study in Tasmania, Australia based on 136 cases of magnetic resonance imaging (MRI)-confirmed MS and 272 community controls, matched on sex and year of birth. Study measures include cumulative exposure to total, older or younger siblings by age 6 years, history of doctor-diagnosed asthma and serological IgG responses to herpes viruses. MS cases were more likely (P = 0.02) than controls to have asthma which began before age of onset of MS symptoms compared to the corresponding age for controls. The absence of younger sibling exposure by age 6 years potentiated (P = 0.04) the association between asthma and MS. Compared to those with younger sibling exposure and no asthma, the adjusted odds ratio for MS for those with asthma and no younger sibling exposure was 7.22 (95% CI: 2.52, 20.65). Early life sibling exposure was associated with altered IgG serological responses to Epstein-Barr virus (EBV) and herpes simplex virus 1 (HSV1) in adulthood. Reduced early life sibling exposure appeared to contribute to the excess of asthma among MS cases by the time of MS onset. MS development may reflect factors that relate to a general immuno-inflammatory up-regulation of immune activity as well as disease specific factors. The link between early life sibling exposure and the immune response to herpes group viral antigens is consistent with a protective role for early life infections.