Abstract Purpose If before cochlear implantation it was possible to assay biomarkers of neuroplasticity, we might be able to identify those children with congenital deafness who, later on, were at risk of poor speech and language rehabilitation outcomes. Methods A group of 40 children aged up to 2 years with DFNB1-related congenital deafness was observed in this prospective cohort study over three follow-up intervals (0, 8, and 18 months) after cochlear implant (CI) activation. Children were assessed for auditory development using the LittlEARS Questionnaire (LEAQ) score, and at the same time, measurements were made of matrix metalloproteinase-9 (MMP-9) plasma levels. Results There were significant negative correlations between plasma levels of MMP-9 at 8-month follow-up and LEAQ score at cochlear implantation (p = 0.04) and LEAQ score at 18-month follow-up (p = 0.02) and between MMP-9 plasma levels at 18-month follow-up and LEAQ score at cochlear implantation (p = 0.04). As already reported, we confirmed a significant negative correlation between MMP-9 plasma level at cochlear implantation and LEAQ score at 18-month follow-up (p = 0.005). Based on this latter correlation, two clusters of good and poor CI performers could be isolated. Conclusions The study shows that children born deaf who have an MMP-9 plasma level of less than 150 ng/ml at cochlear implantation have a good chance of attaining a high LEAQ score after 18 months of speech and language rehabilitation. This indicates that MMP-9 plasma level at cochlear implantation is a good prognostic marker for CI outcome.