Background The incidence of perianal involvement in Crohn’s disease (CD) ranges from 30-40%. Cytokines play a central role in the modulation of the intestinal immune system and can be the target of neutralizing antibodies. Clinical use of anti-TNF is widely established but recent studies suggest that the underlying fistula tract may persist, in spite of a clinical response. IL-12 is a key cytokine that drives the inflammation mediated by T helper 1 cells. Treatment with antibodies against IL-12 was reported to induce clinical responses and remissions in patients with active CD. The aim of our study was to analyze the systemic cytokine network (TNF-α, IL-12, IL-1β, IL-6) in chronic perianal CD, in indeterminate colitis (IC) after restorative proctoclectomy (RPC), in intestinal CD and in healthy controls. Materials and Methods We enrolled 12 patients with chronic perianal CD, 7 with IC submitted to RPC with perianal complications, 7 with intestinal CD and 19 healthy controls. Disease activity was assessed with Crohn and Perianal Disease Activity Indexes (CDAI and PDAI) scores. Cytokines serum levels were quantified in fasting patients with ELISA and immunometric assay. The inflammatory and immunological status was assessed by quantifying erythrocyte sedimentation rate, white blood cell count, platelets blood count (PLT), albuminhaemia and C-reactive protein and pANCA serum levels, respectively. Data were presented as mean ± standard error. Mann-Whitney U two-tailed test and Spearman’s rank correlation test were used. Statistical significance was set at p<0.05. Results Serum TNF-α levels were significantly higher in patients with IC with perianal complications after RPC than perianal CD patients and healthy controls (25,7+/-15,2 vs 21,9+/-13,3 and vs 7,1+/-0,5, p<0.05). Serum TNF-α levels significantly correlated with PDAI and CDAI (R=0.32, p=0.03; R=0.40, p<0.01). Serum IL-12 levels as well as IL-1B ones were similar in all groups and there was no correlation with any of the parameters considered. Serum IL-6 levels did not differ among the four groups and they significantly correlated with PLT and albuminhaemia (R=0.53, p=0.02; R=-0.57, p=0.01). No correlation was found between serum cytokine levels and pANCA. Discussion Our study confirmed that TNF-α plays a major role in the perianal and intestinal CD as demonstrated by the correlation with both activity indexes. Furthermore the significantly higher TNF-α serum levels in patients with IC with perianal complications after RPC suggest the use of anti-TNF in such patients. Moreover, there were no correlations between the serum levels of IL12 and disease activity in chronic perianal CD or IC.