The linear mixed model has become a widely used tool for longitudinal analysis of continuous variables. The use of regression splines in these models offers the analyst additional flexibility in the formulation of descriptive analyses, exploratory analyses and hypothesis‐driven confirmatory analyses. We propose a method for fitting piecewise polynomial regression splines with varying polynomial order in the fixed effects and/or random effects of the linear mixed model. The polynomial segments are explicity constrained by side conditions for continuity and some smoothness at the points where they join. By using a reparameterization of this explicitly constrained linear mixed model, an implicitly constrained linear mixed model is constructed that simplifies implementation of fixed‐knot regression splines. The proposed approach is relatively simple, handles splines in one variable or multiple variables, and can be easily programmed using existing commercial software such as SAS or S‐plus. The method is illustrated using two examples: an analysis of longitudinal viral load data from a study of subjects with acute HIV‐1 infection and an analysis of 24‐hour ambulatory blood pressure profiles. Copyright © 2005 John Wiley & Sons, Ltd.