By detecting focal blood-brain barrier (BBB) breakdown, gadolinium (Gd-DTPA) contrast-enhanced T1-weighted magnetic resonance imaging (MRI) allows assessment of inflammatory activity in multiple sclerosis (MS) and provides a sensitive means of monitoring immunomodulatory therapies in exploratory trials. Serial monthly studies were performed in eight relapsing-remitting and eight secondary progressive patients to assess new and more sensitive techniques for enhanced MRI. Brain and spine imaging was carried out at 1.5-T on two occasions 24-72 h apart using a conventional imaging protocol with T1-weighted MRI at single-dose (0.1 mmol/kg) Gd-DTPA and a potentially more sensitive "modified" protocol with T1-weighted MRI at triple-dose (0.3 mmol/kg) Gd-DTPA (with addition of delay and magnetisation transfer presaturation for brain imaging). For each MRI protocol the total numbers of enhancing lesions (97 paired studies) and new enhancing lesions (81 paired studies) were assessed. The total number of enhancing lesions seen was 347/75 on conventional brain/cord MRI respectively, and 754/123 on modified brain/cord MRI. The respective numbers of new enhancing lesions were 168/40 on conventional and 276/71 on modified scans. Smaller increases were seen in the proportion of active scans using the modified protocol. Sample size calculations showed no reduction in sample sizes required for a parallel group study but a reduced sample size for crossover studies using the modified protocol; the addition of cord to brain imaging did not improve power for either trial design. A combined modified brain and cord imaging protocol markedly improves the detection of areas of focal BBB leakage in MS and may be useful in selected natural history studies. The modified brain protocol reduces sample size requirements for crossover studies but not necessarily for parallel design trials.