Summary. We propose covariance-regularized regression, a family of methods for prediction in high dimensional settings that uses a shrunken estimate of the inverse covariance matrix of the features to achieve superior prediction. An estimate of the inverse covariance matrix is obtained by maximizing the log-likelihood of the data, under a multivariate normal model, subject to a penalty; it is then used to estimate coefficients for the regression of the response onto the features. We show that ridge regression, the lasso and the elastic net are special cases of covariance-regularized regression, and we demonstrate that certain previously unexplored forms of covariance-regularized regression can outperform existing methods in a range of situations. The covariance-regularized regression framework is extended to generalized linear models and linear discriminant analysis, and is used to analyse gene expression data sets with multiple class and survival outcomes.