Summary: We propose the conditional predictive impact (CPI), a consistent and unbiased estimator of the association between one or several features and a given outcome, conditional on a reduced feature set. Building on the knockoff framework of E. Candès et al. [J. R. Stat. Soc., Ser. B, Stat. Methodol. 80, No. 3, 551–577 (2018; Zbl 1398.62335)], we develop a novel testing procedure that works in conjunction with any valid knockoff sampler, supervised learning algorithm, and loss function. The CPI can be efficiently computed for high-dimensional data without any sparsity constraints. We demonstrate convergence criteria for the CPI and develop statistical inference procedures for evaluating its magnitude, significance, and precision. These tests aid in feature and model selection, extending traditional frequentist and Bayesian techniques to general supervised learning tasks. The CPI may also be applied in causal discovery to identify underlying multivariate graph structures. We test our method using various algorithms, including linear regression, neural networks, random forests, and support vector machines. Empirical results show that the CPI compares favorably to alternative variable importance measures and other nonparametric tests of conditional independence on a diverse array of real and synthetic datasets. Simulations confirm that our inference procedures successfully control Type I error with competitive power in a range of settings. Our method has been implemented in an R package, cpi, which can be downloaded from https://github.com/dswatson/cpi.