Objective: The primary objective was to evaluate the safety and immunogenicity of a prototype inactivated, split-virus H5N1 (avian influenza A) vaccine. A secondary objective was to assess the cross-reactivity of immune responses to two variant clade 2 H5N1 strains.Methods: In two randomised, dose comparison, parallel assignment, multicentre trials conducted in Australia, healthy adult volunteers received two doses of 7.5 μg or 15 μg H5 haemagglutinin (HA) vaccine ± AlPO4 adjuvant (phase I trial; N = 400) or two doses of 30 μg or 45 μg H5 HA with AlPO4 adjuvant (phase II trial; N = 400). Revaccination with a booster dose was offered 6 months after dose 2 (phase I trial only). Main outcome measures were the change in immunogenicity at each follow-up visit from baseline, measured using HA inhibition (HI) and virus microneutralisation (MN) assays, and the frequency and nature of adverse events (AEs). Computer generated tables were used to randomly allocate treatments; participants and investigators were blinded to treatment allocation. Findings: All formulations were well-tolerated; no unexpected serious adverse events were reported. Two doses of 30 μg or 45 μg H5 HA adjuvanted formulations elicited the highest immune responses, with considerable MN antibody (≥1:20) persistence up to 6 months post-vaccination. The 7.5 and 15 μg formulations (±adjuvant) were less immunogenic than the higher dose formulations; HI and MN antibody titres decreased to near pre-vaccination levels at 6 months but were restored to post-dose 2 levels after the booster dose. Immune responses in the phase I trial demonstrated modest levels of cross-protective MN antibodies against two currently circulating, distinct clade 2 H5N1 strains. Interpretation: Two doses of prototype 30 μg or 45 μg aluminium-adjuvanted, clade 1 H5N1 vaccines were immunogenic and well-tolerated with considerable 6-month antibody persistence. The prototype H5N1 vaccine also elicited modest levels of cross-protective MN antibodies against variant clade 2 H5N1 strains [ClinicalTrials.gov identifiers: NCT00136331, NCT00320346; Funding: CSL Limited, Australia].