Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disease in children caused by homozygous deletion of the survival motor neuron 1 gene (SMN1). Plastin 3 (PLS3) has been identified as a protective modifier of SMA. We analyzed the levels of PLS3 expression in peripheral blood from 65 children with SMA and 59 healthy controls by using real-time PCR. In healthy controls, younger children (3 years) showed >1.75-fold higher levels of PLS3 expression than did older child cohorts (∼3-6 years, ∼6-12 years and >12 years). In the older female subjects with SMA (>3 years), PLS3 expression was 56.7% lower in type II subjects than in type III patients (P=0.011). When these female subjects carried three copies of SMN2, PLS3 expression was 62.6% lower in the type II subjects than in type III subjects (P=0.008). Moreover, there was a trend toward higher PLS3 expression in older female patients who could walk unaided (>3 years and SMN2 copy number=3) than those who could not. However, these differences were not observed in male subjects examined by SMA clinical type and SMN2 copy number (P>0.05). We concluded that the PLS3 gene may have an age- and gender-specific role in the clinical severity of SMA in children afflicted with this condition.