Quantitative ultrasound techniques using backscattered echoes have had limited success in vivo due to the frequency-dependent attenuation along the entire propagation path masking the frequency dependence of the backscatter. Herein, total attenuation and scatterer size are estimated simultaneously by an analysis of the in vivo backscattered power spectrum using two approaches. The simulations used to evaluate the two approaches used frequencies between 4 and 11 MHz with an effective scatterer radius of 25 μm. The first approach was based on approximations of the in vivo backscattered power spectrum (i.e., assumed Gaussian function), wherein attenuation and size were estimated by assuming each was a Gaussian transformation performed on Gaussian power spectra. The approach had poor accuracy due to the backscattered power spectra not being sufficiently modeled by a Gaussian function. The second approach estimated attenuation and size by fitting a modified reference spectrum to the in vivo backscattered power spectrum without any assumptions about the shape of the spectrum. The accuracy of the size estimate was better than 20% for signal-to-noise ratio >6 dB, window lengths greater than 4 mm, and attenuation between 0 and 1 dB/cm-MHz. However, the precision quickly degraded with increasing noise, increasing attenuation, and decreasing window length.