Background: Patients with limited literacy remain vulnerable to medication errors, especially for instructions that involve negation and food/drug interactions. Pictograms are widely used, but guidance on which visual grammar works best is limited. Methods: We ran a three-arm, randomized experiment with low-literacy adults (N=360) assigned between subjects to one of three icon grammars: A) ISO-style black/white with red slash; B) photo-icon composites with overlaid symbols; C) culturally localized line-art with explicit red “X”/green tick. Each participant judged 12 common label instructions enriched for historically difficult items. The primary outcome was immediate, item-level correct comprehension (binary). Secondary outcomes were response time, confidence, and eye-tracking metrics (time-to-first-fixation, dwell time, scanpath entropy). Analyses used mixed-effects logistic/linear models with participant and item random intercepts (intention-to-treat). Results: Grammar C outperformed A and B on the primary endpoint (overall marginal risk difference vs. A: +10 percentage points, 95% CI +7 to +13; vs. B: +7 pp, by subtraction). Grammar B exceeded A by +3 pp (95% CI 0 to +6). The largest gains for Grammar C occurred on high-risk items: “Not by mouth” (A 62%, B 68%, C 78%) and “Do not take with dairy” (A 55%, B 60%, C 72%); timing/handling items also improved (e.g., “Every 8 hours”: A 69%, B 73%, C 81%). Eye-tracking corroborated these differences: median time-to-first-fixation on critical regions was 1.42 s (A), 1.31 s (B), and 1.08 s (C), indicating more efficient visual search under Grammar C. Results were consistent across literacy strata and languages; no subgroup showed harm. A 48-hour retention subset (n=210) maintained the C > B > A pattern. Conclusions: How pictograms are drawn matters. Culturally localized line-art with explicit negation cues produced faster and more accurate comprehension, especially for negation and interaction instructions. We provide a practice checklist—use explicit negation near the action/object; pair action+object+context; prefer simplified line-art—that can be embedded in label-printing systems without added counseling time. Future pragmatic trials should link these comprehension gains to adherence, error reduction, and cost outcomes.