The microbubble contrast agent destruction/replenishment technique has been widely applied to ultrasound-based blood flow estimation. The rate of increase of the time-intensity curve (TIC) due to microbubbles flowing into the region of interest as measured from B-mode images closely reflects the flow velocity. In this study, we monitored microbubble replenishment by a proposed new approach called the time-Nakagami-parameter curve (TNC) obtained from Nakagami-parameter images for quantifying the flow velocity. The feasibility of using the TNC to estimate the flow was evaluated in computer simulations of the TIC and TNC for flow velocities from 10 to 30 cm/s under an ultrasound frequency of 5 MHz. The clutter effects on the TIC and TNC were explored in amore realistic situation by carrying out phantom measurements of 25 MHz. The rates of increase of the TIC and TNC were expressed by the rate constants beta1 and betaN of a monoexponential model, respectively. The average beta1 increased from 38 to 110 s(-1) as the flow velocity increased from 10 to 30 cm/s (r = 0.98), and the average betaN increased from approximately 40 to 120 s(-1) for the same increase in flow velocity (r = 0.98). The p-value between the results of beta1 and betaN as a function of flow velocity was 0.77. These results represent that betaN quantifies the flow velocity similarly to the conventional beta1. In particular, both the simulation and experimental results revealed that the TNC method conditionally tolerates the presence of nonperfused areas (e.g., surrounding tissues or vessel walls) in the region of interest without requiring application of an additional wall filter to cancel the influences of clutter echoes on the flow estimation. These findings suggest that the TNC-based technique may be a potential method as a complementary tool for the conventional TIC technique to improve the estimation of blood flow.