Under a standard assumption in complexity theory (NP not in P/poly), we demonstrate a gap between the minimax prediction risk for sparse linear regression that can be achieved by polynomial-time algorithms, and that achieved by optimal algorithms. In particular, when the design matrix is ill-conditioned, the minimax prediction loss achievable by polynomial-time algorithms can be substantially greater than that of an optimal algorithm. This result is the first known gap between polynomial and optimal algorithms for sparse linear regression, and does not depend on conjectures in average-case complexity.