The precision of pharmacokinetic parameter estimates from several least squares parameter estimation methods are compared. The methods can be thought of as differing with respect to the way they weight data. Three standard methods, Ordinary Least Squares (OLS-equal weighting), Weighted Least Squares with reciprocal squared observation weighting [WLS(y-2)], and log transform OLS (OLS(ln))--the log of the pharmacokinetic model is fit to the log of the observations--are compared along with two newer methods, Iteratively Reweighted Least Squares with reciprocal squared prediction weighting (IRLS,(f-2)), and Extended Least Squares with power function "weighting" (ELS(f-xi)--here xi is regarded as an unknown parameter). The values of the weights are more influenced by the data with the ELS(f-xi) method than they are with the other methods. The methods are compared using simulated data from several pharmacokinetic models (monoexponential, Bateman, Michaelis-Menten) and several models for the observation error magnitude. For all methods, the true structural model form is assumed known. Each of the standard methods performs best when the actual observation error magnitude conforms to the assumption of the method, but OLS is generally least perturbed by wrong error models. In contrast, WLS(y-2) is the worst of all methods for all error models violating its assumption (and even for the one that does not, it is out performed by OLS(ln)). Regarding the newer methods, IRLS(f-2) improves on OLS(ln), but is still often inferior to OLS. ELS(f-xi), however, is nearly as good as OLS (OLS is only 1-2% better) when the OLS assumption obtains, and in all other cases ELS(f-xi) does better than OLS. Thus, ELS(f-xi) provides a flexible and robust method for estimating pharmacokinetic parameters.