Objective: The phenotype of systemic lupus erythematosus (SLE) in Asian Indians is more severe as compared with that in Caucasians. The reason is not clear. In this context, we studied serum levels of interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), interleukin-4 (IL-4) and interlekin-10 (IL-10). Their interrelations and correlation with SLEDAI scores were evaluated. Materials and methods: Forty patients with active SLE and 40 controls were studied. The mean SLEDAI score and anti-ds DNA level of the patients were 21.45 ± 8.61 and 176.68 ± 81.31 (IU/ml), respectively. Cytokines were estimated by enzyme-linked immunosorbent assay. Results: In controls, the levels of IFN-γ were highest, followed by TNF-α, IL-10 & IL-4. In patients, however, the levels of TNF-α were highest, followed by IFN-γ, IL-10 & IL-4. IL-10 and IL-4 correlated negatively, and IFN-γ and TNF-α correlated positively with the SLEDAI scores. As compared with controls, in patients, the mean values of TNF-α, IL-10 and TNF-α/IL-10 ratio were higher by 6.9, 2.9 and 2.3 times, respectively (p < 0.001). Significant positive correlation was found between these two cytokines in patients (r = 0.327, p < 0.05) but not in controls. The levels and ratio of IL-4 and IFN-γ were comparable between patients and controls. These two cytokines correlated negatively both in controls (r = −0.358, p < 0.05) and patients (r = −0.990, p < 0.001). The ratio of TNF-α/IL-4 was 4.2 times higher, and those of IFN-γ/IL-4 and IFN-γ/IL-10 were 1.89 and 3.40 times lower in patients as compared with controls. A positive correlation between IL-10 and IL-4 (r = 0.345, p < 0.05) and a negative correlation between IL-10 and IFN-γ (r = −0.382, p < 0.05) were observed only in patients. Conclusion: This study showed a distinct profile of cytokine imbalance in patients with SLE from the northern plains of India. The levels, ratios and correlations of cytokines in patients suggested significant deviation from normal. Correlations of cytokines with SLEDAI scores indicated that TNF-α contributes significantly to the pathological manifestations of SLE in patients from the region. A detailed study is warranted.