Interferon-beta (IFN-beta) therapy for multiple sclerosis (MS) is associated with a potential for induction of neutralizing antibodies (NAbs). Because immune reactivity depends on changes in lipoprotein metabolism, we investigated whether plasma lipoprotein profiles could be associated with the development of NAbs. Thirty-one female MS patients treated with subcutaneously administered IFN-beta were included. Demographic and clinical characteristics were compared between NAbs response groups using t tests for continuous and logistic regression analysis and Fisher’s exact tests for categorical data, respectively. Multivariate logistic regression was used to evaluate the effect of potential confounders. Patients who developed NAbs had lower apoE levels before treatment, 67 (47–74) mg/L median (interquartile range), and at the moment of NAb analysis, 53 (50–84) mg/L, in comparison to those who remained NAb-negative, 83 (68–107) mg/L, P = 0.03, and 76 (66–87) mg/L, P = 0.04, respectively. When adjusting for age and smoking for a one-standard deviation decrease in apoE levels, a 5.6-fold increase in the odds of becoming NAb-positive was detected: odds ratios (OR) 0.18 (95% CI 0.04–0.77), P = 0.04. When adjusting for apoE, smoking habit became associated with NAb induction: OR 5.6 (95% CI 1.3–87), P = 0.03. These results suggest that apoE-containing lipoprotein metabolism and, possibly, tobacco smoking may be associated with risk of NAb production in female MS patients treated with IFN-beta.