BackgroundNo study has directly compared the various treatment options for canine atopic dermatitis and their effects on skin barrier.Hypothesis/ObjectivesTo compare prednisone, oclacitinib, ciclosporin and lokivetmab treatment of atopic dermatitis.AnimalsNineteen atopic beagle dogs.Methods and materialsControlled, blinded study. Dogs were challenged with allergen twice weekly and randomized to oclacitinib, ciclosporin, lokivetmab, prednisone or no treatment for four weeks. Dermatitis and pruritus were assessed at baseline and after each challenge. Transepidermal water loss (TEWL) and hydration were measured at baseline, Day (D)14 and D28 (pinnae, axilla, groin). Area under the curve (AUC) was calculated for Canine Atopic Dermatitis Extent and Severity Index, 3rd iteration (CADESI‐03), pruritus, TEWL and hydration. For CADESI, the AUC of the first two weeks was compared to that of the last two weeks.ResultsFor CADESI, restricted maximum‐likelihood ANOVA showed effect of time (P = 0034) and group x time interaction (P = 0.0169). In the first two weeks, prednisone and oclacitinib were significantly lower than controls (P = 0.019 and P = 0.015, respectively). Lokivetmab prevented flares. Due to variability, no significance differences in pruritus were observed among groups. The TEWL increased with time in controls (P = 0.0237) and ciclosporin (P = 0.04, axilla, D28 versus D0) but not in the oclacitinib and lokivetmab groups. CADESI‐03 correlated with TEWL (P = 0.0043) and pruritus (P = 0.0283). Hydration did not correlate with any parameters. Hydration decreased in controls and prednisone group (axilla, D14 versus D0, P = 0.004 and P = 0.027, respectively). AUC for hydration, over time, was higher for lokivetmab and oclacitinib than controls (P = 0.014 and P = 0.04, respectively).Conclusions and clinical importanceLokivetmab prevented flares when given before challenge. Oclacitinib and lokivetmab have some positive effects on skin barrier parameters.