The influence of pregnancy in multiple sclerosis has been a matter of controversy for a long time. The Pregnancy in Multiple Sclerosis (PRIMS) study was the first large prospective study which aimed to assess the possible influence of pregnancy and delivery on the clinical course of multiple sclerosis. We report here the 2‐year post‐partum follow‐up and an analysis of clinical factors which might predict the likelihood of a relapse in the 3 months after delivery. The relapse rate in each trimester up to the end of the second year post‐partum was compared with that in the pre‐pregnancy year. Clinical predictors of the presence or absence of a post‐partum relapse were analysed by logistic regression analysis. Using the best multivariate model, women were classified as having or not having a post‐partum relapse predicted, and this was compared with the observed outcome. The results showed that, compared with the pre‐pregnancy year, there was a reduction in the relapse rate during pregnancy, most marked in the third trimester, and a marked increase in the first 3 months after delivery. Thereafter, from the second trimester onwards and for the following 21 months, the annualized relapse rate fell slightly but did not differ significantly from the relapse rate recorded in the pre‐pregnancy year. Despite the increased risk for the 3 months post‐partum, 72% of the women did not experience any relapse during this period. Confirmed disability continued to progress steadily during the study period. Three indices, an increased relapse rate in the pre‐pregnancy year, an increased relapse rate during pregnancy and a higher DSS (Kurtzke’s Disability Status Scale) score at pregnancy onset, significantly correlated with the occurrence of a post‐partum relapse. Neither epidural analgesia nor breast‐feeding was predictive. When comparing the predicted and observed status, however, only 72% of the women were correctly classified by the multivariate model. In conclusion, the results for the second year post‐partum confirm that the relapse rate remains similar to that of the pre‐pregnancy year, after an increase in the first trimester following delivery. Women with greater disease activity in the year before pregnancy and during pregnancy have a higher risk of relapse in the post‐ partum 3 months. This is, however, not sufficient to identify in advance women with multiple sclerosis who are more likely to relapse, especially for planning therapeutic trials aiming to prevent post‐partum relapses.