Although anti-Smith (Sm) antibody is a highly specific antibody for systemic lupus erythematosus (SLE), the significance of anti-Sm antibody in patients with SLE is unclear. This study aimed to evaluate the association between anti-Sm antibodies and disease activity in patients with new-onset SLE. We included patients who were tested for anti-Sm antibodies at SLE diagnosis and within 12 months after diagnosis. SLE disease activity index (SLEDAI) was obtained at the time of the anti-Sm antibody test. The baseline disease activity was compared between patients with and without anti-Sm antibodies. The longitudinal association between disease activity and anti-Sm antibodies was also evaluated in total patients and in those with anti-Sm antibodies. Among 92 patients who were tested for anti-Sm antibodies at SLE diagnosis, 67 and another 67 patients were followed up for the presence of anti-Sm antibodies at 6 and 12 months, respectively. Although the baseline SLEDAI was comparable in patients with and without anti-Sm antibodies, the serum level of anti-Sm antibody was significantly correlated with SLEDAI (P = 0.003). At 12 months, anti-Sm antibody positivity was associated with higher SLEDAI and anti-dsDNA titer (P = 0.002, both). In addition, the changes in anti-Sm antibody titer over 12 months were correlated with the alterations in SLEDAI (P = 0.029).Anti-Sm antibody was associated with the baseline disease activity and the alteration of disease activity in patients with new-onset SLE. Monitoring of anti-Sm antibody titer may help assess the disease activity in SLE.