The need for oral, cost-effective treatment for complicated skin and skin structure infections (cSSSIs) due to methicillin-resistant Staphylococcus aureus (MRSA) was addressed by the non-inferiority comparisons of oral minocycline plus rifampicin with linezolid. In the AIDA multicenter, open label, randomized, controlled clinical trial, hospitalized adults with cSSSI and documented MRSA were randomly assigned at a 2:1 ratio to either oral 600mg rifampicin qd plus 100mg minocycline bid or oral 600mg linezolid bid for 10 days. The primary endpoint was the clinical cure rate in the clinically evaluable (CE) population at the test-of-cure visit (14 days). Non-inferiority was confirmed if the lower confidence limit (CI) did not fall below the accepted error margin of 15%. The study is registered with EudraCT number 2014-001276-56. 123 patients recruited between November 2014 and January 2017 were randomly assigned to treatment (81 patients to minocycline plus rifampicin and 42 patients to linezolid). Cure rates were 78.% (46/59, 90% CI 67.3-86.5) and 68.6% (24/35, 90% CI 53.4-81.3), respectively (P=0.337). The percent difference in cure rates was 9.4% (90% CI-7.2 to 26.8%). Minocycline plus rifampicin combination was deemed non-inferior to linezolid as the lower CI was-7.2% i.e. smaller than the accepted error margin of-15%. Although statistically not significant, the overall rate of adverse events was higher in the linezolid group (47.6%, 20/42 versus 38.3%, 31/81). Oral minocycline plus rifampicin was non-inferior to oral linezolid treatment providing alternative oral treatment for cSSSI. The EU Seventh Research Framework Programme.