Objective To identify the occurrence and determinants of protocol-publication discrepancies in clinical drug trials. Study Design and Setting All published clinical drug trials reviewed by the Dutch institutional review boards in 2007 were analyzed. Discrepancies between trial protocols and publications were measured among key reporting aspects. We evaluated the association of trial characteristics with discrepancies in primary endpoints by calculating the risk ratio (RR) and 95% confidence interval (CI). Results Of the 334 published trials, 32 (9.6%) had a protocol/publication discrepancy in the primary endpoints. Among the subgroup of randomized controlled trials (RCTs; N = 204), 12 (5.9%) had a discrepancy in the primary endpoint. Investigator-initiated trials with and without industry (co-) funding were associated with having discrepancies in the primary endpoints compared with industry-sponsored trials (RR 3.7; 95% CI 1.4–9.9 and RR 4.4; 95% CI 2.0–9.5, respectively). Furthermore, other than phase 1–4 trials (vs. phase 1; RR 4.6; 95% CI 1.1–19.3), multicenter trials were also conducted outside the European Union (vs. single center; RR 0.2; 95% CI 0.1–0.6), not prospectively registered trials (RR 3.3; 95% CI 1.5–7.5), non-RCTs (vs. superiority RCT; RR 2.4; 95% CI 1.2–4.8) and, among the RCTs, crossover compared with a parallel group design (RR 3.7; 95% CI 1.1–12.3) were significantly associated with having discrepancies in the primary endpoints. Conclusions Improvement in completeness of reporting is still needed, especially among investigator-initiated trials and non-RCTs. To eliminate undisclosed discrepancies, trial protocols should be available in the public domain at the same time when the trial is published.