Imiquimod (IMQ)-induced skin inflammation is currently the most widely accepted psoriasis animal model, however, it features several limitations. We have modified the IMQ-model to minimize its systemic effects towards effectively maintaining the characteristic skin reactions. The original protocol (OP) uses 62.5 mg Aldara cream (or vaseline) on the shaved back skin of mice for 4 days. In contrast, in our modified protocol (MP) 25 mg Aldara and vaseline are applied simultaneously in separate Finn chambers over the dorsal skin of mice. In both the OP and MP groups, histology showed unequivocal hallmarks of psoriasiform dermatitis. Additionally, skin scaling and blood perfusion values were similar. While Aldara elicited significantly increased skin thickness in the MP group, significant weight loss, spleen enlargement, increased inflammatory cytokine levels in plasma, and treatment related death were only observed in the OP group. Our new method reproduces psoriatic skin alterations highlighting considerably reduced systemic inflammatory reactions. Possessing psoriasiform and control skin areas on the same mouse also reduces inter-individual differences. Additionally, the new method permits prolonged IMQ treatment studies to mimic the chronic nature of psoriasis. Finally, our experimental approach may also be used in other mouse models, to prevent the undesired systemic effects of topically applied drugs.