Purpose. Population pharmacokinetics of a fast release diclofenac were assessed with special focus on pharmacodynamic implications. Methods. In a double blind four-way crossover study, 20 healthy volunteers received orally 50 and 100 mg diclofenac-Na effervescent ('fast-release NSAID'), 50 mg diclofenac tablets ('control'), or placebo. Population pharmacokinetics of the fast release diclofenac were assessed using a nonlinear mixed effects modeling approach (NON-MEM). Analgesic effects were investigated by means of an experimental pain model based on both pain-ratings and cortical evoked potentials after specific stimulation of nasal nociceptors with short pulses of gaseous CQ₂. Results. Pharmacokinetics of fast release diclofenac were best described by a two-compartment population model, with an estimated terminal half-life of 1.2 hours. Pharmacokinetics of diclofenac tablets were highly variable and a population pharmacokinetic model could not be obtained. As an indication of an early onset of analgesic effects, 100 mg fast release diclofenac but not the tablets significantly reduced the amplitudes of pain- related evoked potentials at 30 min after administration. Conclusions. Earlier drug absorption and lower pharmacokinetic variability of the fast- release formulation are likely to be preserved in a population.