Abstract Iterative reconstructions are increasingly used for clinical PET studies owing to the better noise properties compared with filtered backprojection (FBP). The purpose of the present study was to compare ordered subsets expectation maximization (OSEM) iterative reconstruction with FBP as input for statistical parametric mapping (SPM) analysis of PET activation studies. Two phantom studies were performed simulating both motor and cognitive tasks and acquiring data with both high and low statistics. In contrast to clinical studies, where no a priori information is known, phantom studies allow for an accurate and detailed comparison between different reconstruction techniques. The significance of “activations” during “tasks” was determined using SPM99 software. Using region of interest analysis of SPM results, it was found that the maximum and average t values within each hot spot of the phantom were higher for OSEM than for FBP. In addition, OSEM4 × 16 (4 iterations, 16 subsets) produced fewer false-positive voxels than FBP, OSEM1 × 16 and OSEM2 × 16. In conclusion, for PET activation studies use of OSEM4 × 16 seems to give the best tradeoff between signal detection and noise reduction.