To determine changes over time of serum levels of 25-hydroxy vitamin D (25(OH)D) in Mexican patients with SLE and their relationship with disease activity. Longitudinal and observational study. Women with SLE were included. Serum levels of 25(OH)D were measured at baseline and after two years; the disease activity was measured with MEX-SLEDAI. Patients with initial suboptimal levels of 25(OH)D received supplements or increased doses of calcitriol. 105 women with SLE were included, mean age 49.4 ± 11 years. Serum levels of 25(OH)D were higher at two years (baseline 20 ± 6.8 vs. follow-up 22.7 ± 7.7; p = < 0.001). There were no differences between disease activity scores at baseline and two years (baseline 1.7 ± 1.9 vs. follow-up 1.1 ± 1.7; p = 0.7). Serum levels of 25(OH)D did not correlate with disease activity during the follow up, p = 0.7. No correlation was found between changes in MEX-SLEDAI scores and serum levels of 25(OH)D, p = 0.87. Mexican women with SLE had increased serum levels of 25(OH)D. No correlation between serum levels of 25(OH)D and disease activity was found.