Summary: P(enalized)-splines and fractional polynomials (FPs) have emerged as powerful smoothing techniques with increasing popularity in applied research. Both approaches provide considerable flexibility, but only limited comparative evaluations of the performance and properties of the two methods have been conducted to date. Extensive simulations are performed to compare FPs of degree 2 (FP2) and degree 4 (FP4) and two variants of P-splines that used generalized cross validation (GCV) and restricted maximum likelihood (REML) for smoothing parameter selection. The ability of P-splines and FPs to recover the “true” functional form of the association between continuous, binary and survival outcomes and exposure for linear, quadratic and more complex, non-linear functions, using different sample sizes and signal to noise ratios is evaluated. For more curved functions FP2, the current default setting in implementations for fitting FPs in R, STATA and SAS, showed considerable bias and consistently higher mean squared error (MSE) compared to spline-based estimators and FP4, that performed equally well in most simulation settings. FPs however, are prone to artefacts due to the specific choice of the origin, while P-splines based on GCV reveal sometimes wiggly estimates in particular for small sample sizes. Application to a real dataset illustrates the different features of the two approaches.