This study was conducted to investigate the frequency and significance of some antinuclear autoantibodies in Omani patients with systemic lupus erythematosus (SLE). Anti-nuclear antibodies (ANA), anti-double stranded-DNA (anti-dsDNA), and anti-Smith (anti-Sm) autoantibodies were investigated in 60 Omani patients clinically diagnosed with SLE according to the American College of Rheumatology Criteria. The SLE group included 57 females and 3 males with an average age of 26 years. In addition, a group of 60 healthy Omanis (26 females and 34 males; average age 25 years) was used as a control. ANA patterns and autoantibody profile were assayed by indirect immunofluorescence assay using Hep-2 cells and liver/kidney/stomach tissue, respectively. Anti-dsDNA were examined by enzyme-linked immunosorbent assays; anti-Sm antibodies were measured by immunoblotting technique. Out of the 60 SLE patients, 59/60 (98.3%) were seropositive for ANA. Anti-dsDNA and anti-Sm each was detected in 50/60 (83.3%) of the Omani patients. The homogenous pattern of ANA was detected in 30/60 (50%) of patients, whereas the frequency of fine-speckled and coarse-speckled was 16/60 (26.7%) and 6/60 (10%), respectively. High titers (≥ 1:320) of ANA was detected in 56/60 (93.3%) of SLE patients. High titers of anti-Sm were detected in 22/60 (33.3%) of patients. High titers (>100 IU/ml) of anti-dsDNA were detected in 40/60 (66.7%) of patients. In the control group, ANA were detected in 8/60 (13.3%) but at low titers, whereas anti-dsDNA and anti-Sm were not detected in the healthy control group. This study shows that anti-Sm is as important as the anti-dsDNA for confirming the diagnosis of SLE and that anti-Sm occurs at a much higher frequency (83.3%) than that reported in other populations indicating the importance of this specific autoantibody for the diagnosis and possibly prognosis of Omani SLE patients.