Groups of female MRL/MpJ‐lpr/lpr mice received either saline or FK506 (tacrolimus; 2mg/kg intraperitoneally) three times weekly, cyclophosphamide (CY; 20mg/kg) once monthly, or both drugs from 8 weeks of age. Median survival for untreated and CY‐treated mice was 26 weeks, and for FK506‐ and FK5O6 + CY‐treated groups was ± 44 weeks. Severity of skin lesions and lymph node hyperplasia was markedly reduced by the drug combination, whereas either drug alone was less effective. FK506 or CY alone delayed the onset of proteinuria, but by 24 weeks all of these animals were positive. In contrast, drug combination reduced the prevalence of proteinuria to ± 60% throughout the 44 weeks of study. Sequential monitoring of peripheral blood lymphocytes revealed that combination therapy but not monotherapy markedly reduced the proportion of atypical CD3⁺ B220⁺ and CD3⁺CD4^‐CD8^‐ T cells. Neither FK506 nor CY affected the reduction in IL‐2 and IL‐4 mRNA levels observed in lymph nodes of diseased animals compared with normals. Although the drug combination also did not affect IL‐2 mRNA levels, IL‐4 mRNA transcripts were increased six‐fold compared with saline‐treated controls. IL‐10 and interferon‐gamma (IFN‐γ) mRNAs were induced by FK506, CY and by the drug combination. Serum levels of anti‐dsDNA antibodies were reduced in all treatment groups. These data demonstrate improved efficacy of combined T and B cell‐directed immunosuppression in murine lupus, associated with marked inhibition of atypical T cells and selective augmentation of IL‐4 within the affected lymphoid tissue.