Current clinical applications of dynamic contrast-enhanced MRI (DCE-MRI) are based on the extravasation of relatively small contrast agents (SCAs). SCAs are considered disadvantageous, as they require high image sampling rates. Medium-sized contrast agents (MCAs) leak more slowly into tissue and allow longer dynamic acquisition times, enabling improved image quality. The influence of molecular size on the reliability of pharmacokinetic parameters, including the transfer constant K(trans), was investigated. Computer simulations were performed, with in vivo measured arterial input functions (AIFs), to determine the bias and variance of pharmacokinetic parameters as a function of contrast agent size, sampling frequency, noise level, and acquisition time. Better reliability of all parameters was obtained for the MCA compared to the SCA. To obtain similar variance (10%) in K(trans), the sampling frequency for the SCA (28 min(-1)) had to be 20 times faster than for the MCA (1.3 min(-1)). Optimal reliability in parameter estimation required longer acquisition times for MCAs (13 min for the fraction of the extravascular extracellular space into which the contrast agent distributes (v(e)) and 5 min for K(trans)) than for SCAs (1.7 min for K(trans) and v(e)). Reliable estimation of the fractional blood plasma volume (v(p)) was only achieved with MCAs. In conclusion, MCAs provided superior reliability for pharmacokinetic parameter estimation compared to SCAs.